Medical device coating with a biocompatible layer

ABSTRACT

Medical devices with a hydrogel layer covalently attached to a portion of the outer surface of the medical device are provided along with methods for applying the coating. The hydrogel layer can include a first polymer species comprising polyethylene glycol (PEG) and a second polymer species. Examples of the second polymer species include PEG and polyacrylamide (PAM). The first and second species can be at least partially cross-linked. Methods for forming the hydrogel coatings on the medical devices are provided including nucleophilic conjugate reactions, such as Click reactions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application62/089,734 filed on Dec. 9, 2014 entitled “Medical Device Coating with aBiocompatible Layer”, the disclosure of which is herein incorporated byreference in its entirety.

This application is also related to PCT/US2013/056703 filed on Aug. 27,2013 titled “Contact Lens with a Hydrophilic Layer” and published as WO2014/035912 and to PCT/US2014/065588 filed on Nov. 14, 2014 titled“Contact Lens with a Hydrophilic Layer” and published as WO 2015/073758,each of which are incorporated by reference in their entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

FIELD

Embodiments of the technology relate to medical devices with improvedbiocompatibility and surface properties and methods for making theimproved devices. More particularly, the technology relates to medicaldevices with a highly stable hydrogel layer covering the surface.

BACKGROUND

The use of such biomaterial articles as substitute blood vessels,synthetic and intraocular lenses, electrodes, catheters, orthopedicimplants and the like in and onto the body is a rapidly developing areaof medicine. A primary impediment to the use of such biomaterial deviceshas been the lack of satisfactory biocompatibility of the devicesurfaces. The uncoated surfaces of catheters made from plastics, forexample, often stimulate rapid thrombogenic action. Various plasmaproteins play a role in initiating platelet and fibrin deposition onplastic surfaces and these actions, and the inflammatory reaction thatfollows, can lead to the loss of function of the device. A “medicaldevice” may be defined as a material that is substantially insoluble inbody fluids and that is designed and constructed to be placed in or ontothe body or to contact fluid of the body. Catheters, grafts, stents,implants, wound dressings, cardiac valves and intravenous tubing areexamples of medical devices.

A medical device surface can desirably have the followingcharacteristics: The device surface will not generally induceundesirable reactions in the body such as blood clotting, tissue death,tumor formation, allergic reaction, foreign body reaction (rejection) orinflammatory reaction. The device surface can be fabricated andsterilized easily such as by autoclave heat sterilization. The devicesurface does not substantially alter the function of the underlyingdevice during the time that it remains implanted in or in contact withthe body, whether it be an hour or a lifetime. The surface or surfacecoating is nontoxic to the tissues it is in contact with. In the case ofa device with an optical function, the surface will be optically clearto allow proper function.

As used herein, the solid surface of a biomaterial is characterized as“biocompatible” if it is capable of functioning or existing in contactwith biological fluid and/or tissue of a living organism with a netbeneficial effect on the living organism. Long-term biocompatibility isdesired for the purpose of reducing disturbance of the host organism.

A number of approaches have been suggested to improve thebiocompatibility of implantable items. One approach has been to modifythe surface of a biomaterial to prevent undesirable protein adhesion byproviding the biomaterial with a protein resistant surface. For example,a contact lens may bind proteins on the lens to create protein depositsin the eye area. Additionally, the lens can cause structural changesincluding protein denaturation that can elicit an immune response suchas tearing, reddening, or swelling in the ocular region. Accordingly,contemplated embodiments provide for medical devices and methods ofmaking devices with improved resistance to undesirable proteininteractions and other interactions at the surface.

SUMMARY OF THE DISCLOSURE

In general, in one embodiment, a medical device including an outersurface and a hydrogel layer covalently attached to at least a portionof the outer surface, the hydrogel layer adapted to contact a bodytissue or fluid, wherein the hydrogel layer comprises a biocompatiblepolymer population having a first hydrophilic polymer species includingpolyethylene glycol (PEG) and a second hydrophilic polymer speciesincluding polyacrylamide, the first hydrophilic polymer species being atleast partially covalently cross-linked to the second hydrophilicpolymer species, wherein the medical device may not be a contact lens.

This and other embodiments can include one or more of the followingfeatures. The device can be configured to be implantable within amammalian body. The device can be a stent configured to keep a cavityopen. The stent can be configured to keep a blood vessel, bile duct,intestine, nasal passage or cavity, sinus cavity, or intraocular channelopen. The device can be a sensor, camera, vital sign monitor, drug depotdevice, neurostimulator, ultrasound, silicone implant, saline implant,hernia mesh, penile implant, orthopedic rod or plate or pin or nails,pacemaker, cardiac valve, ear tube, aneurysm coil, or intraocular lens.The device can be a test strip. The device can be a drug, salivary,urine, blood or semen test strip. The device can be a tool configured tobe inserted within a mammalian body. The device can be a catheter,trocar, endoscope, or laparoscope. The device can be configured to beused externally on a mammalian body. The device can be configured foruse as a bandage, wound dressing, external sensor, hearing aid, orartificial skin. The outer surface of the device can include one or moreof: glass, plastic, titanium, nitinol, polyethylene, polypropylene,polyvinyl chloride, polytetraflouroethylene, polydimethylsiloxane,polyethylene terephthalate, polyamides, polyether urethane, polyetherurethane urea, polystyrene, polycarbonate, polysulfones, polymethylmethacrylate, poly 2-hydroxyethylmethacrylate, polyvinylalcohol,polyglycolic acid, polycaprolactone, polylactic acid, polyortho ester,cellulose acetate, collagen, or silk. The outer surface of the devicecan consists essentially of a material selected from the groupconsisting of: glass, plastic, titanium, nitinol, polyethylene,polypropylene, polyvinyl chloride, polytetraflouroethylene,polydimethylsiloxane, polyethylene terephthalate, polyamides, polyetherurethane, polyether urethane urea, polystyrene, polycarbonate,polysulfones, polymethyl methacrylate, poly 2-hydroxyethylmethacrylate,polyvinylalcohol, polyglycolic acid, polycaprolactone, polylactic acid,polyortho ester, cellulose acetate, collagen, or silk. The first speciescan include a reactive electrophilic group or a reactive nucleophilicgroup and the second species can include a reactive electrophilic groupor a reactive nucleophilic group complementary to the first species, thereactive electrophilic group and the reactive nucleophilic group can beadapted to react to thereby form cross-links between the first speciesto the second species. The reactive electrophilic group can be selectedfrom the group consisting of: amino-reactive groups, sulfhydryl-reactivegroups, carboxyl groups, hydroxyl groups, haloalkyl groups, dienophilegroups, aldehyde or ketone groups, alkenes, epoxides, andphosphoramidites. The reactive nucleophilic group can be selected fromthe group consisting of: amines, amino-reactive groups, sulfhydryl,sulfhydryl-reactive groups, carboxyl groups, hydroxyl groups, haloalkylgroups, dienophile groups, aldehyde or ketone groups, alkenes, epoxides,and phosphoramidites. At least one of the reactive electrophilic groupof the first species or the reactive electrophilic group of the secondspecies can be covalently linked to the outer surface of the device. Thehydrogel layer substantially can surround the outer surface of thedevice. The hydrogel layer or the hydrogel layer and device can besubstantially optically clear. The hydrogel layer can be adapted toallow optical transmission through the hydrogel layer to the device. Thehydrogel layer can be adapted to attenuate x-ray transmission. Thehydrogel layer can be adapted to enable diffusion of biologic molecules,glucose, solutes, polymers, drugs. The hydrogel layer can include athickness between about 5 nm to about 30 nm. The hydrogel layer caninclude a thickness below about 100 nm. The hydrogel layer can include athickness less than about 50 nm. The hydrogel layer can include athickness less than about 1 micron. The hydrogel layer can include amaximum thickness of about 10 microns. A first portion of the hydrogellayer can include a first thickness different from a second thickness ofa second portion of the hydrogel layer. Each of the first and secondhydrophilic polymer species can be a branched species having a branchcount between two to twelve branch arms. The first hydrophilic polymerspecies can include a reactive electron pair accepting group and thesecond hydrophilic polymer species can include a reactive nucleophilicgroup, the reactive electron pair accepting group and the reactivenucleophilic group can be adapted to react to thereby form cross-linksbetween the first hydrophilic polymer species to the second hydrophilicpolymer species. The hydrogel layer has a lower coefficient of frictionthan an underlying device surface. The hydrogel can have a relativeprotein resistance compared to an underlying device surface. Thehydrogel layer can include between about 80% to about 98% water byweight.

In general, in one embodiment, a medical device including an outersurface covered by an outer biocompatible polymer layer, wherein thebiocompatible polymer layer includes a first polyethylene glycol (PEG)macromer subpopulation having an electron pair accepting moiety and asecond macromer subpopulation including polyacrylamide having a firstnucleophilic reactive moiety, wherein the first and second macromersubpopulations are cross-linked.

This and other embodiments can include one or more of the followingfeatures. The device can be configured to be implantable within amammalian body. The device can be a stent configured to keep a cavityopen. The stent can be configured to keep a blood vessel, bile duct,intestine, nasal passage or cavity, sinus cavity, or intraocular channelopen. The device can be a glucose sensor, endoscopic camera, vital signmonitor, drug depot device, neurostimulator, ultrasound, breast implant,hernia mesh, penile implant, orthopedic rod or plate or pin or nails,pacemaker, cardiac valve, ear tube, aneurysm coil, or intraocular lens.The device can be a tool configured to be inserted within a mammalianbody. The device can be a catheter, trocar, endoscope, or laparoscope.The device can be configured to be used externally on a mammalian body.The device can be configured for use as a bandage, wound dressing,external sensor, hearing aid, or artificial skin. The medical device maynot be a contact lens. The outer surface of the device can include orconsist essentially of any of the following: glass, plastic, titanium,nitinol, polyethylene, polypropylene, polyvinyl chloride,polytetraflouroethylene, polydimethylsiloxane, polyethyleneterephthalate, polyamides, polyether urethane, polyether urethane urea,polystyrene, polycarbonate, polysulfones, polymethyl methacrylate, poly2-hydroxyethylmethacrylate, polyvinylalcohol, polyglycolic acid,polycaprolactone, polylactic acid, polyortho ester, cellulose acetate,collagen, or silk. The outer surface of the device can consistessentially of a material selected from the group consisting of: glass,plastic, titanium, nitinol, polyethylene, polypropylene, polyvinylchloride, polytetraflouroethylene, polydimethylsiloxane, polyethyleneterephthalate, polyamides, polyether urethane, polyether urethane urea,polystyrene, polycarbonate, polysulfones, polymethyl methacrylate, poly2-hydroxyethylmethacrylate, polyvinylalcohol, polyglycolic acid,polycaprolactone, polylactic acid, polyortho ester, cellulose acetate,collagen, or silk. The biocompatible polymer layer can be attached tothe device by a covalent linkage between the electron pair acceptingmoiety of the first hydrophilic polymer macromer and a secondnucleophilic reactive moiety on a surface of the device. The firstspecies can include a reactive electrophilic group or a reactivenucleophilic group and the second species can include a reactiveelectrophilic group or a reactive nucleophilic group complementary tothe first species, the reactive electrophilic group and the reactivenucleophilic group can be adapted to react to thereby form cross-linksbetween the first species to the second species. The reactiveelectrophilic group can be selected from the group consisting of:amino-reactive groups, sulfhydryl-reactive groups, carboxyl groups,hydroxyl groups, haloalkyl groups, dienophile groups, aldehyde or ketonegroups, alkenes, epoxides, and phosphoramidites. The reactivenucleophilic group can be selected from the group consisting of: amines,amino-reactive groups, sulfhydryl, sulfhydryl-reactive groups, carboxylgroups, hydroxyl groups, haloalkyl groups, dienophile groups, aldehydeor ketone groups, alkenes, epoxides, and phosphoramidites. At least oneof the reactive electrophilic group of the first species or the reactiveelectrophilic group of the second species can be covalently linked tothe outer surface of the device. The biocompatible polymer layer caninclude between about 50% and about 98% water by weight. Thebiocompatible polymer layer can include between about 85% and about 98%water by weight. The hydrogel layer can include a thickness betweenabout 5 nm to about 30 nm. The hydrogel layer can include a thicknessbelow about 100 nm. The hydrogel layer can include a thickness less thanabout 50 nm. The hydrogel layer can include a thickness less than about1 micron. The hydrogel layer can include a maximum thickness of about 10microns. The biocompatible polymer layer can further include at leastone active agent. The at least one active agent can be selected from thegroup consisting of a protein, drug, nanoparticle, cell, or solute.

In general, in one embodiment, a method of making a medical device witha hydrophilic polymer layer including reacting an outer surface of themedical device with a first polymer species of a hydrophilic polymersolution, wherein the first polymer species comprises a moiety at afirst portion that forms a covalent attachment to the outer surface ofthe device and reacting the first polymer species of the hydrophilicpolymer solution with a second polymer species of the hydrophilicpolymer solution, the second polymer species including a moiety thatforms a covalent bond to a second portion of the first polymer speciesin a second covalent reaction thereby forming a hydrogel coatingincluding the first polymer species and the second polymer species atleast partially cross-linked.

This and other embodiments can include one or more of the followingfeatures. The device can be configured to be implantable within amammalian body. The device can be a stent configured to keep a cavityopen. The stent can be configured to keep a blood vessel, bile duct,intestine, nasal passage or cavity, sinus cavity, or intraocular channelopen. The hydrophilic polymer layer can reduce thrombosis of the stent.The device can be a glucose sensor, endoscopic camera, vital signmonitor, drug depot device, neurostimulator, ultrasound, breast implant,hernia mesh, penile implant, orthopedic rod or plate or pin or nails,pacemaker, cardiac valve, ear tube, aneurysm coil, or intraocular lens.The hydrophilic polymer layer can reduce an immune system reactionagainst the implant. The device can be a tool configured to be insertedwithin a mammalian body. The device can be a catheter, trocar,endoscope, or laparoscope. The hydrophilic polymer layer can increaseblood flow through the catheter when the catheter can be inserted into amammalian body. The device can be configured to be used externally on amammalian body. The device can be configured for use as a bandage, wounddressing, external sensor, hearing aid, or artificial skin. The medicaldevice may not be a contact lens. The outer surface of the device caninclude or consist essentially of any of the following: glass, plastic,titanium, nitinol, stainless steel, polyethylene, polypropylene,polyvinyl chloride, polytetraflouroethylene, polydimethylsiloxane,polyethylene terephthalate, polyamides, polyether urethane, polyetherurethane urea, polystyrene, polycarbonate, polysulfones, polymethylmethacrylate, poly 2-hydroxyethylmethacrylate, polyvinylalcohol,polyglycolic acid, polycaprolactone, polylactic acid, polyortho ester,cellulose acetate, collagen, or silk. The outer surface of the devicecan consist essentially of a material selected from the group consistingof: glass, plastic, titanium, nitinol, stainless steel, polyethylene,polypropylene, polyvinyl chloride, polytetraflouroethylene,polydimethylsiloxane, polyethylene terephthalate, polyamides, polyetherurethane, polyether urethane urea, polystyrene, polycarbonate,polysulfones, polymethyl methacrylate, poly 2-hydroxyethylmethacrylate,polyvinylalcohol, polyglycolic acid, polycaprolactone, polylactic acid,polyortho ester, cellulose acetate, collagen, or silk. The reactingsteps can be performed at a temperature between about 15 degrees Celsiusand about 100 degrees Celsius. The reacting steps can be performed at atemperature between about 20 degrees Celsius and about 40 degreesCelsius. The reacting steps can be performed at a pH between about 7 andabout 11. The hydrophilic polymer layer can be substantially opticallyclear. The covalent attachment between the outer surface of the deviceand the first portion of the first polymer species can be formed by afirst nucleophilic conjugate reaction. The second covalent reaction canbe a second nucleophilic conjugate reaction. The partial cross-linkingcan be between an electrophilic moiety of the first species and anucleophilic moiety of the second species in a nucleophilic conjugatereaction. The hydrophilic polymer layer can include a first speciesselected from the group consisting of: polyethylene glycol (PEG),phosphorylcholine, poly(vinyl alcohol), poly(vinylpyrrolidinone),poly(N-isopropylacrylamide) (PNIPAM), polyacrylamide (PAM),poly(2-oxazoline), polyethylenimine (PEI), poly(acrylic acid),polymethacrylate, polyelectrolytes, hyaluronic acid, chitosan,chondroitin sulfate, alginate, hydroxypropylmethylcellulose, anddextran. The hydrophilic polymer layer can include a second speciesselected from the group consisting of: polyethylene glycol (PEG),phosphorylcholine, poly(vinyl alcohol), poly(vinylpyrrolidinone),poly(N-isopropylacrylamide) (PNIPAM), polyacrylamide (PAM),poly(2-oxazoline), polyethylenimine (PEI), poly(acrylic acid),polymethacrylate, polyelectrolytes, hyaluronic acid, chitosan,chondroitin sulfate, alginate, hydroxypropylmethylcellulose, anddextran. The hydrophilic polymer layer can include a first speciesincluding polyethylene glycol (PEG). The hydrophilic polymer layer caninclude a second species including polyacrylamide. The first species caninclude a reactive electrophilic group or a reactive nucleophilic groupand the second species can include a reactive electrophilic group or areactive nucleophilic group complementary to the first species, thereactive electrophilic group and the reactive nucleophilic group can beadapted to react to thereby form cross-links between the first speciesto the second species. The reactive electrophilic group can be selectedfrom the group consisting of: amino-reactive groups, sulfhydryl-reactivegroups, carboxyl groups, hydroxyl groups, haloalkyl groups, dienophilegroups, aldehyde or ketone groups, alkenes, epoxides, andphosphoramidites. The reactive nucleophilic group can be selected fromthe group consisting of: amines, amino-reactive groups, sulfhydryl,sulfhydryl-reactive groups, carboxyl groups, hydroxyl groups, haloalkylgroups, dienophile groups, aldehyde or ketone groups, alkenes, epoxides,and phosphoramidites. At least one of the reactive electrophilic groupof the first species or the reactive electrophilic group of the secondspecies can be covalently linked to the outer surface of the device. Themethod can further include modifying the outer surface of the device toform the plurality of reactive nucleophilic sites or a plurality ofelectrophilic sites on the outer surface. The modifying step can includeexposing the outer surface of the medical device to a gas plasmatreatment. The method can further include adding a bifunctional monomeror a polymer to a prepolymerization mixture used to form the hydrophilicpolymer layer. The bifunctional monomer or polymer may not substantiallychange the optical properties of the contact medical device. Thebifunctional monomer or polymer can provide additional nucleophilic orelectrophilic reactive sites on the surface of the device. The methodcan further include modifying an outer surface of the device. Modifyingthe outer surface of the device can include one or more of: pHadjustment, plasma activation, light activation, activation of theliquid monomer mix, wet activation, and adding a monomer that reactswith the outer surface of the device that still leaves reactive sites.Both of the first and second nucleophilic conjugate reactions can beClick reactions. The Click reaction can be a conjugate additionreaction. Both of the first and second nucleophilic conjugate additionreactions can be 1,4-nucleophilic addition reactions. The first andsecond nucleophilic conjugate addition reactions can be bothMichael-type reactions. The reacting steps can be performed at a pHbetween about 5 and about 11. The method can further include adding atleast one active agent to the hydrophilic polymer layer. The at leastone active agent can be selected from the group consisting of aUV-absorbing agent, a visibility tinting agent, an antimicrobial agent,a bioactive agent, a leachable lubricant, a leachable tear-stabilizingagent, or any mixture thereof. The antimicrobial agent can includesilver nanoparticles. The hydrophilic polymer layer can have a thicknessof less than about 50 nm.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 shows a catheter in accordance with an embodiment. FIG. 1B is across section view of the catheter illustrated in FIG. 1A.

FIG. 2A shows prosthetic implants for replacing a hip joint.

FIG. 2B shows an implantable pacemaker.

FIG. 2C shows an implantable glucose sensor.

FIG. 2D shows a stent.

FIGS. 3A-3B show a first polymer species and a second polymer specieswith respective reactive groups A and N.

FIGS. 4A-4B show a reaction between a sulfonyl and thiol group.

FIGS. 5A-5C show schematically a biocompatible polymer having twospecies covalently attached to a lens core.

FIGS. 6A-6C show a captive bubble test.

FIG. 7 shows an activated lens surface.

FIG. 8 is a schematic diagram of a first and second reaction withprincipal reactants.

FIGS. 9A-9D show more details of reactants and reactions depicted inFIG. 8.

FIGS. 10A-10B are flow diagrams of exemplary methods described.

FIGS. 11A-11B show a schematic viewing of a continuously stirred tankreactor.

FIGS. 12A-12B show a method of producing lenses with bilateral hydrogellayers differing in depth or composition.

FIG. 13 is a graph illustrating captive bubble contact angle results forcoatings applied to various devices in accordance with some embodiments.

DETAILED DESCRIPTION

Methods for forming biocompatible coatings are disclosed herein. Thebiocompatible coatings can be formed on a surface of a medical device.The biocompatible coating can improve the compatibility of the medicaldevice with the biological tissue that the device contacts. Theprocesses disclosed herein advantageously allow for rapid, high yieldreactions to coat the medical devices. The reactions do not producetoxic byproducts, which is a large advantage when medical devices arecoated. The reaction can also take place in an aqueous solution therebyfacilitating coating coverage of the device surfaces. In someembodiments the medical device is not a contact lens.

The properties of the biocompatible coating can be tailored based on thespecific medical device application. For example, the coating can haveimproved protein resistance and antithrombogenic properties on vascularstents and on catheters or other devices used in the vasculature. Forexample, the catheter coating can result in increased blood flow throughthe catheter. The biocompatible coating can also improve wettability,lubricity, protein resistance, and antithrombogenicity of catheterdevices.

The medical device can be used in on or on mammalian bodies. In someembodiments the medical device is used within the mammalian body. Insome embodiments the medical device is implanted in the mammalian body.In some embodiments the medical device contacts an external surface ofthe mammalian body.

FIG. 1A illustrates a catheter 10 in accordance with an embodiment. Thecatheter 10 has a handle 11 and flexible outer shaft 14. The catheter 10has a lumen configured to receive a guidewire 12. FIG. 1B illustrates across section of the catheter 10 showing a cross section of theguidewire 12 within a guidewire lumen 15. A biocompatible coating 17 isformed on an outer surface 16 of the catheter 10.

FIG. 2A shows prosthetic implants for replacing a hip joint. Theprosthesis includes a metal ball and stem engaged with the femur and anacetabular prosthesis engaged with the hip bone. The biocompatiblecoating can be formed on the exterior surfaces of the acetabularprosthesis and the metal ball and stem prosthesis. The biocompatiblecoating can improve the lubricity of the prosthesis surfaces anddecrease friction between the metal ball and acetabular prosthesis.

FIG. 2B shows an implantable pacemaker 20A. The implantable pacemaker20A includes an electronics compartment 21A, insulated wire, andelectrode 22B. The electronics compartment 21A, insulated wire, andelectrode 22B of the implantable pacemaker 20A can be partially or fullycoated with the biocompatible coatings described herein.

FIG. 2C shows an implantable glucose sensor 20C. The glucose sensor 20Ccan have an outer surface 21C with biocompatible coating 23C.

FIG. 2D shows a stent 20D. The stent 20D has an outer surface 21D with abiocompatible coating 23D. The stent 20D is illustrated in a tubularconfiguration. Other stent shapes and configurations are possible. Thestents can be used in vascular applications, gastrointestinalapplications, and in other hollow body lumens.

A. Biocompatible Polymer Layer

As used herein, the term “biocompatible layer” or “hydrogel layer” mayrefer to a single continuous layer or various coated portions on themedical device.

Although shown in FIG. 1B as a single biocompatible layer covering anexterior of the medical device, it is to be appreciated that in somecases, only a portion of the medical device (e.g. a single surface or apart of a surface) may be coated by a biocompatible polymer layer. Insome cases, the biocompatible layer may only coat one of the medicaldevice surfaces such as the surface in direct contact with the tissue.Moreover, the layer may not coat the entire area of the surface.

Additionally, other contemplated embodiments may include two or morenoncontiguous biocompatible polymer layers. For example, a firstbiocompatible polymer layer may at least partially cover one surfacewhile a second biocompatible polymer layer may at least partially covera second surface. The first and second biocompatible polymer layer maynot touch or share a boundary with one another.

In certain embodiments, the arrangement between the medical device andthe surrounding hydrogel or biocompatible layer may be understood as alayered structure with a biocompatible polymer layer attached to anouter surface of a medical device. The biocompatible polymer layer maybe placed on either of the anterior or posterior surfaces. In somevariations, the biocompatible layer may only cover a portion of themedical device.

In other cases, the arrangement may include a first biocompatiblepolymer layer on one side of the medical device, a second biocompatiblepolymer layer on another side of the medical device. The core layerbeing a middle layer between the two biocompatible polymer layers. Thefirst and second layers may share a boundary (e.g. contiguous layers) ormay form separate independent layers (e.g. noncontiguous layers).

In some cases, the layered arrangement on a medical device can beestablished by fluorescence analysis methods as described in Qui et al,U.S. Pat. Appl. Nos. 201200026457 and 201200026458 or alternatively, byscanning electron microscopy.

Additionally, the biocompatible layer may have relatively uniformdimensions, compositions, and mechanical properties throughout. Thebiocompatible layer may have a substantially uniform thickness, watercontent, and chemical composition throughout the layer. In someembodiments, the biocompatible layer has a substantially homogeneouscomposition and a substantially uniform depth and/or thickness. In someembodiments the hydrogel layer substantially surrounds the outer surfaceof the medical device. In other embodiments the hydrogel layer can beapplied to only a portion of the medical device or only the portion ofthe medical device that contacts the body tissue or fluid.

As can be appreciated, uniformity is not required and may not bedesirable for all situations. In some cases, a single layer may includeportions having different characteristics including dimensions,composition, and/or mechanical properties. For example, a portion of thelayer may have a different thickness than another portion, which mayresult in varying water content between the two portions.

In some cases the medical device can include multiple hydrogel layercoatings applied to different portions of the device. The differentcoatings can have different properties. The different properties can betailored the specific portion of the device to which the coating isapplied. In some examples a first portion of the hydrogel layer can havea first thickness and a second portion of the hydrogel layer can have asecond thickness with the first thickness and second thickness beingdifferent.

Similarly, where two or more biocompatible layers are used, thebiocompatible polymer layers may share or differ in any characteristics.For example, the medical device may be asymmetrically layered with thebiocompatible polymer. The depth/thickness of the resultingbiocompatible polymer layers may vary between the layers on opposingsides of the medical device. This can result in, for example, differentmechanical characteristics between the anterior facing side of thecoated medical device and the posterior side.

In some variations, the average thickness of the biocompatible polymerlayer may range between about 25 nm and about 50 nm. In particularembodiments, the biocompatible layer has a thickness of about 1 nm toabout 500 nm. In an exemplary embodiment, the thickness of thebiocompatible layer is between about 1 nm and about 10 microns, orbetween about 1 nm and about 50 nm, or between about 10 nm and about 200nm, or between about 25 nm and about 200 nm, or between about 25 nm andabout 100 nm, or between about 5 nm and about 50 nm, or between about 10nm and about 50 nm, or between about 10 nm and about 35 nm, or betweenabout 10 nm and about 25 nm, or between about 1 nm and about 10 nm. Insome embodiments, the hydrogel layer comprises a thickness below about100 nm. In some embodiments, the hydrogel layer comprises a thicknessbelow about 50 nm. In some embodiments, the hydrogel layer comprises athickness below about 40 nm. In some embodiments, the hydrogel layer hasa thickness between about 5 nm to about 30 nm. In some embodiments, thehydrogel layer has a thickness less than about 1 micron. In someembodiments, the hydrogel layer has a thickness less than about 10microns.

In further variations, the thickness or depth of the hydrogel layer mayalso be expressed in terms of the fold-multiple over a layer that couldbe represented as a molecular monolayer. In some embodiments, thebiocompatible layer has a thickness of that exceeds the nominalthickness of a molecular monolayer by at least five-fold. For example,in some cases the biocompatible polymer layer is formed from PEGmolecules that have a PEG monolayer radius of about 5 nm. The PEGcontaining biocompatible polymer layer may have a thickness of about 50nm, which results in a layer thickness or depth that is approximately10-fold greater than the PEG monolayer radius.

Without limitation, the thickness of the anterior or posterior surfaceof a coated medical device of the invention can be determined byScanning Electron Microscopy, AFM or fluorescence microscopy analysis ofa cross section of the medical device in fully hydrated state asdescribed herein.

Additionally, the biocompatible layer may be understood to have avolume. In some cases, a first portion of the layer may have firstvolume V1 and a second portion of the layer may have a second volume V2.The volume may be calculated based on an estimated surface area of thelayer. A total volume may also be understood to be the volume of asingle biocompatible layer (e.g. a layer covering an entire implant) ora sum of various layers with corresponding volumes.

Volume calculations may be based on an estimated surface area ofapproximately 1.25 square centimeters, in the example of a contact lenson each side of the lens core. In some cases, the biocompatible polymerlayer has a volume in the range of about 15 nl to about 1.5 μl. In othervariations, a volume range of about 7.5 nl to about 150 nl correspondsto an enveloping biocompatible thickness range of about 25 nm to about500 nm. Other volume ranges are possible for coatings on medical deviceshaving different geometries. For example, the layer on a coated catheterforms an annular shape. The coating volume can be calculated using thedimensions of the annular shape.

For water content of the biocompatible layer, in some embodiments, thewater content is between about 50% and about 98% water by weight. Insome embodiments, the water content is between about 80% and about 98%water by weight. In some embodiments, the water content is between about85% and about 98% water by weight. In other embodiments, thebiocompatible layer includes between about 85% and about 95% water byweight. Additionally, the water content of the biocompatible layer maybe expressed either by total water content or by a weight/volumepercent. The polymer content of the biocompatible layer may be describedalso by a weight/volume percent.

The biocompatible layer may also include a biocompatible polymerpopulation having one or more subpopulations or species. In some cases,one or more species or subpopulations are cross-linked to form thebiocompatible polymer layer. The biocompatible polymer layer precursorsmay be provided in a solution containing the cross-linkable material.Once cross-linked, the one or more species form the biocompatiblepolymer coating.

In one variation, the biocompatible layer includes a first polymerspecies and a second polymer species that are at least partiallycross-linked together to form the biocompatible layer. Additionally, thepolymer species or subpopulation may include linear and/or branchedcomponents. A branched species may include a polymer having a branchcount ranging from 2-arm to 12-arm branching. In other embodiments, thebranched species may include starred branching with about 100 branchesor more.

Referring to the FIG. 3A, a first branched polymer species 51 and asecond branched polymer species 52 are schematically shown. The firstbranched polymer species 51 has four branch arms with reactivefunctional group A. The second branched polymer species 52 is shownhaving four branch arms with a reactive functional group N. In someembodiments, a reactive moiety A of the first polymer species 51 isadapted to react with a reactive moiety B of the second polymer species52. The reaction between moieties A and B may form a covalent cross-linkbetween the first and second polymer species. FIG. 3B depicts the firstand second species 51, 52 cross-linked by an A-N moiety formed by areaction between the reactive group A of the first polymer species and areactive group B of a second polymer species. In some embodiments, thecross-linking action between one or more polymer and/or macromer speciesforms the biocompatible polymer layer. For example, cross-linking one ormore polymer species in a polymer solution may form a hydrogel withdesirable characteristics for coating the medical device.

As can be appreciated, the cross-linking mechanism and/or reaction for afirst and second polymer species may include any number of suitablemethods known in the art including photochemical or thermalcross-linking. In some cases, cross-linking may occur throughnucleophilic conjugate reaction, Michael-type reaction (e.g. 1,4addition), and/or Click reaction between respective reactive groups onmore than one polymer species in the biocompatible layer.

Any suitable polymers may be used for the biocompatible polymerpopulation in the biocompatible layer. In some cases, the polymerpopulation includes species derived from polyethylene glycol (PEG),phosphorylcholine, poly(vinyl alcohol), poly(vinylpyrrolidinone),poly(N-isopropylacrylamide) (PNIPAM), polyacrylamide (PAM),poly(2-oxazoline), polyethylenimine (PEI), poly(acrylic acid), acrylicpolymers such as polymethacrylate, polyelectrolytes, hyaluronic acid,chitosan, and dextran. In some embodiments a PEG polymer species ormacromer is used in the biocompatible coating. In some embodiments a PAMpolymer species or macromer is used in the biocompatible coating. Insome embodiments a PEG polymer species or macromer and a PAM species ormacromer are used in the biocompatible coating.

Additionally, any suitable reactive moieties may be used for the polymerspecies and subpopulations including reactive functional groups (e.g.reactive nucleophilic groups and electron pair acceptor) that react toform covalent linkages between polymer species or subpopulations to formthe biocompatible polymer layer described.

1. Reactive Functional Groups

Reactive functional groups and classes of reactions useful in covalentlinking and cross-linking are generally known in the art. In some cases,suitable classes of reactions with reactive functional groups includethose that proceed under relatively mild conditions. These include, butare not limited to nucleophilic substitutions (e.g., reactions of aminesand alcohols with acyl halides and activated esters), electrophilicsubstitutions (e.g., enamine reactions) and additions to carbon-carbonand carbon-heteroatom multiple bonds (e.g., Michael reactions andDiels-Alder reactions). These and other useful reactions are discussed,for example, in: March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley& Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, AcademicPress, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS;Advances in Chemistry Series, Vol. 198, American Chemical Society,Washington, D.C., 1982.

a) Amines and Amino-Reactive Groups

In one embodiment, the reactive functional group is a member selectedfrom amines, such as a primary or secondary amine, hydrazines,hydrazides, and sulfonylhydrazides. Amines can, for example, beacylated, alkylated or oxidized. Useful non-limiting examples ofamino-reactive groups include N-hydroxysuccinimide (NHS) esters,sulfo-NHS esters, imidoesters, isocyanates, isothiocyanates,acylhalides, arylazides, p-nitrophenyl esters, aldehydes, sulfonylchlorides and carboxyl groups.

NHS esters and sulfo-NHS esters react preferentially with the primary(including aromatic) amino groups of the reaction partner. The imidazolegroups of histidines are known to compete with primary amines forreaction, but the reaction products are unstable and readily hydrolyzed.The reaction involves the nucleophilic attack of an amine on the acidcarboxyl of an NHS ester to form an amide, releasing theN-hydroxysuccinimide.

Imidoesters are the most specific acylating reagents for reaction withthe amine groups of e.g., a protein. At a pH between 7 and 10,imidoesters react only with primary amines. Primary amines attackimidates nucleophilically to produce an intermediate that breaks down toamidine at high pH or to a new imidate at low pH. The new imidate canreact with another primary amine, thus crosslinking two amino groups, acase of a putatively monofunctional imidate reacting bifunctionally. Theprincipal product of reaction with primary amines is an amidine that isa stronger base than the original amine. The positive charge of theoriginal amino group is therefore retained. As a result, imidoesters donot affect the overall charge of the conjugate.

Isocyanates (and isothiocyanates) react with the primary amines of theconjugate components to form stable bonds. Their reactions withsulfhydryl, imidazole, and tyrosyl groups give relatively unstableproducts.

Acylazides are also used as amino-specific reagents in whichnucleophilic amines of the reaction partner attack acidic carboxylgroups under slightly alkaline conditions, e.g. pH 8.5.

Arylhalides such as 1,5-difluoro-2,4-dinitrobenzene react preferentiallywith the amino groups and phenolic groups of the conjugate components,but also with its sulfhydryl and imidazole groups.

p-Nitrophenyl esters of carboxylic acids are also useful amino-reactivegroups. Although the reagent specificity is not very high, α- andε-amino groups appear to react most rapidly.

Aldehydes react with primary amines of the conjugate components.Although unstable, Schiff bases are formed upon reaction of the aminogroups with the aldehyde. Schiff bases, however, are stable, whenconjugated to another double bond. The resonant interaction of bothdouble bonds prevents hydrolysis of the Schiff linkage. Furthermore,amines at high local concentrations can attack the ethylenic double bondto form a stable Michael addition product. Alternatively, a stable bondmay be formed by reductive amination.

Aromatic sulfonyl chlorides react with a variety of sites of theconjugate components, but reaction with the amino groups is the mostimportant, resulting in a stable sulfonamide linkage.

Free carboxyl groups react with carbodiimides, soluble in both water andorganic solvents, forming pseudoureas that can then couple to availableamines yielding an amide linkage. Yamada et al., Biochemistry 1981, 20:4836-4842, e.g., teach how to modify a protein with carbodiimides.

b) Sulfhydryl and Sulfhydryl-Reactive Groups

In another embodiment, the reactive functional group is a memberselected from a sulfhydryl group (which can be converted to disulfides)and sulfhydryl-reactive groups. Useful non-limiting examples ofsulfhydryl-reactive groups include maleimides, alkyl halides, acylhalides (including bromoacetamide or chloroacetamide), pyridyldisulfides, and thiophthalimides.

Maleimides react preferentially with the sulfhydryl group of theconjugate components to form stable thioether bonds. They also react ata much slower rate with primary amino groups and imidazole groups.However, at pH 7 the maleimide group can be considered asulfhydryl-specific group, since at this pH the reaction rate of simplethiols is 1000-fold greater than that of the corresponding amine.

Alkyl halides react with sulfhydryl groups, sulfides, imidazoles, andamino groups. At neutral to slightly alkaline pH, however, alkyl halidesreact primarily with sulfhydryl groups to form stable thioether bonds.At higher pH, reaction with amino groups is favored.

Pyridyl disulfides react with free sulfhydryl groups via disulfideexchange to give mixed disulfides. As a result, pyridyl disulfides arerelatively specific sulfhydryl-reactive groups.

Thiophthalimides react with free sulfhydryl groups to also formdisulfides.

c) Other Reactive Functional Groups

Other exemplary reactive functional groups include:

-   -   (a) carboxyl groups and various derivatives thereof including,        but not limited to, N-hydroxybenztriazole esters, acid halides,        acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl,        alkenyl, alkynyl and aromatic esters;    -   (b) hydroxyl groups, which can be converted to esters, ethers,        aldehydes, etc.;    -   (c) haloalkyl groups, wherein the halide can be displaced with a        nucleophilic group such as, for example, an amine, a carboxylate        anion, thiol anion, carbanion, or an alkoxide ion, thereby        resulting in the covalent attachment of a new group at the site        of the halogen atom;    -   (d) dienophile groups, which are capable of participating in        Diels-Alder reactions such as, for example, maleimido groups;    -   (e) aldehyde or ketone groups, such that subsequent        derivatization is possible via formation of carbonyl derivatives        such as, for example, imines, hydrazones, semicarbazones or        oximes, or via such mechanisms as Grignard addition or        alkyllithium addition;    -   (f) alkenes, which can undergo, for example, cycloadditions,        acylation, Michael addition, etc;    -   (g) epoxides, which can react with, for example, amines and        hydroxyl groups;    -   (h) phosphoramidites and other standard functional groups useful        in nucleic acid synthesis and    -   (i) any other functional group useful to form a covalent bond        between the functionalized ligand and a molecular entity or a        surface.        d) Reactive Functional Groups with Non-specific Reactivities

In addition to the use of site-specific reactive moieties, the presentinvention contemplates the use of non-specific reactive functionalgroups. Non-specific groups include photoactivatable groups, forexample. Photoactivatable groups are ideally inert in the dark and areconverted to reactive species in the presence of light. In oneembodiment, photoactivatable groups are selected from macromers ofnitrenes generated upon heating or photolysis of azides.Electron-deficient nitrenes are extremely reactive and can react with avariety of chemical bonds including N—H, O—H, C—H, and C═C. Althoughthree types of azides (aryl, alkyl, and acyl derivatives) may beemployed, arylazides are presently preferred. The reactivity ofarylazides upon photolysis is better with N—H and O—H than C—H bonds.Electron-deficient arylnitrenes rapidly ring-expand to formdehydroazepines, which tend to react with nucleophiles, rather than formC—H insertion products. The reactivity of arylazides can be increased bythe presence of electron-withdrawing substituents such as nitro orhydroxyl groups in the ring. Such substituents push the absorptionmaximum of arylazides to longer wavelength. Unsubstituted arylazideshave an absorption maximum in the range of 260-280 nm, while hydroxy andnitroarylazides absorb significant light beyond 305 nm. Therefore,hydroxy and nitroarylazides may be preferable since they allow to employless harmful photolysis conditions for the affinity component thanunsubstituted arylazides.

In an exemplary embodiment, photoactivatable groups are selected fromfluorinated arylazides. The photolysis products of fluorinatedarylazides are arylnitrenes, all of which undergo the characteristicreactions of this group, including C—H bond insertion, with highefficiency (Keana et al., J. Org. Chem. 55: 3640-3647, 1990).

In another embodiment, photoactivatable groups are selected frombenzophenone residues. Benzophenone reagents generally give highercrosslinking yields than arylazide reagents.

In another embodiment, photoactivatable groups are selected from diazocompounds, which form an electron-deficient carbene upon photolysis.These carbenes undergo a variety of reactions including insertion intoC—H bonds, addition to double bonds (including aromatic systems),hydrogen attraction and coordination to nucleophilic centers to givecarbon ions.

In still another embodiment, photoactivatable groups are selected fromdiazopyruvates. For example, the p-nitrophenyl ester of p-nitrophenyldiazopyruvate reacts with aliphatic amines to give diazopyruvic acidamides that undergo ultraviolet photolysis to form aldehydes. Thephotolyzed diazopyruvate-modified affinity component will react likeformaldehyde or glutaraldehyde.

It is well within the abilities of a person skilled in the art to selecta reactive functional group, according to the reaction partner. As anexample, an activated ester, such as an NHS ester can be a usefulpartner with a primary amine. Sulfhydryl reactive groups, such asmaleimides can be a useful partner with SH, thiol, groups.

Additional exemplary combinations of reactive functional groups found ona compound of the invention and on a targeting moiety (or polymer orlinker) are set forth in Table 1.

TABLE 1 Chemical Chemical Functionality 1 Functionality 2 LinkageHydroxy Carboxy Ester Hydroxy Carbonate Amine Carbamate SO₃ Sulfate PO₃Phosphate Carboxy Acyloxyalkyl Ketone Ketal Aldehyde Acetal HydroxyAnhydride Mercapto Mercapto Disulfide Carboxy Acyloxyalkyl ThioetherCarboxy Thioester Carboxy Amino amide Mercapto Thioester CarboxyAcyloxyalkyl ester Carboxy Acyloxyalkyl amide Amino Acyloxyalkoxycarbonyl Carboxy Anhydride Carboxy N-acylamide Hydroxy Ester HydroxyHydroxymethyl ketone ester Hydroxy Alkoxycarbonyl oxyalkyl Amino CarboxyAcyloxyalkylamine Carboxy Acyloxyalkylamide Amino Urea Carboxy AmideCarboxy Acyloxyalkoxycarbonyl Amide N-Mannich base Carboxy Acyloxyalkylcarbamate Phosphate Hydroxy Phosphate oxygen ester Amine PhosphoramidateMercapto Thiophosphate ester Ketone Carboxy Enol ester SulfonamideCarboxy Acyloxyalkyl sulfonamide Ester N-sulfonyl-imidate

One skilled in the art will readily appreciate that many of theselinkages may be produced in a variety of ways and using a variety ofconditions. For the preparation of esters, see, e.g., March supra at1157; for thioesters, see, March, supra at 362-363, 491, 720-722, 829,941, and 1172; for carbonates, see, March, supra at 346-347; forcarbamates, see, March, supra at 1156-57; for amides, see, March supraat 1152; for ureas and thioureas, see, March supra at 1174; for acetalsand ketals, see, Greene et al. supra 178-210 and March supra at 1146;for acyloxyalkyl derivatives, see, PRODRUGS: TOPICAL AND OCULAR DRUGDELIVERY, K. B. Sloan, ed., Marcel Dekker, Inc., New York, 1992; forenol esters, see, March supra at 1160; for N-sulfonylimidates, see,Bundgaard et al., J. Med. Chem., 31:2066 (1988); for anhydrides, see,March supra at 355-56, 636-37, 990-91, and 1154; for N-acylamides, see,March supra at 379; for N-Mannich bases, see, March supra at 800-02, and828; for hydroxymethyl ketone esters, see, Petracek et al. Annals NYAcad. Sci., 507:353-54 (1987); for disulfides, see, March supra at 1160;and for phosphonate esters and phosphonamidates.

The reactive functional groups can be chosen such that they do notparticipate in, or interfere with, the reactions necessary to assemblethe reactive ligand analogue. Alternatively, a reactive functional groupcan be protected from participating in the reaction by the presence of aprotecting group. Those of skill in the art will understand how toprotect a particular functional group from interfering with a chosen setof reaction conditions. For examples of useful protecting groups, seeGreene et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley &Sons, New York, 1991.

Generally, prior to forming the linkage between the compound of theinvention and the targeting (or other) agent, and optionally, the linkergroup, at least one of the chemical functionalities will be activated.One skilled in the art will appreciate that a variety of chemicalfunctionalities, including hydroxy, amino, and carboxy groups, can beactivated using a variety of standard methods and conditions. Forexample, a hydroxyl group of the ligand (or targeting agent) can beactivated through treatment with phosgene to form the correspondingchloroformate, or p-nitrophenylchloroformate to form the correspondingcarbonate.

In an exemplary embodiment, the invention makes use of a targeting agentthat includes a carboxyl functionality. Carboxyl groups may be activatedby, for example, conversion to the corresponding acyl halide or activeester. This reaction may be performed under a variety of conditions asillustrated in March, supra pp. 388-89. In an exemplary embodiment, theacyl halide is prepared through the reaction of the carboxyl-containinggroup with oxalyl chloride. The activated agent is combined with aligand or ligand-linker arm combination to form a conjugate of theinvention. Those of skill in the art will appreciate that the use ofcarboxyl-containing targeting agents is merely illustrative, and thatagents having many other functional groups can be conjugated to theligands of the invention.

Referring to FIG. 4A, in some embodiments, the reactive functionalgroups include thiol and sulfonyl moieties. The reactive nucleophilicgroup may be a thiol group adapted to react to a sulfonyl group thatfunctions as an electron pair accepting moiety. Where a first polymerspecies contains a reactive thiol group and a second polymer speciescontains a reactive sulfonyl group, the cross-linkage between the firstand second species may be formed through a thioether moiety (FIG. 4B).

In other variations, one or more polymer species in the biocompatiblelayer are covalently linked through a sulfonyl moiety such as, but notlimited to, an alkylene sulfonyl moiety, a dialkylene sulfonyl moiety,an ethylene sulfonyl moiety, or a diethylene sulfonyl moiety. In furthervariations, one or more polymer species in the biocompatible layer arecovalently linked through a sulfonyl moiety and a thioether moiety, oran alkylene sulfonyl moiety and a thioether moiety, or a dialkylenesulfonyl moiety and a thioether moiety, or an ethylene sulfonyl moietyand a thioether moiety, or a diethylene sulfonyl moiety and a thioethermoiety.

In further variations, the one or more polymer species in thebiocompatible layer are covalently linked through an ester moiety, oralkylene ester moiety, or an ethylene ester moiety, or a thioethermoiety, or an ester moiety and a thioether moiety, or an alkylene estermoiety and a thioether moiety, or an ethylene ester moiety and athioether moiety.

In some embodiments, the ratio of the reactive subpopulations in thebiocompatible polymer population is approximately 1 to 1. In otherembodiments, the concentration of one of the subpopulations or speciesexceeds another species by about 10% to about 30%. For example, theconcentration of a polymer species with an electron pair acceptingmoiety may exceed another polymer species with a reactive nucleophilicgroup.

Additionally, where the concentration of a first and second polymerspecies are approximately 1 to 1, the relative number of reactivemoieties for each species may be approximately the same or different.For example, a polymer species may have more sites having an electronpair accepting moiety compared to the number of reactive sites on theother polymer species carrying the nucleophilic group. This may beaccomplished, for example, by having a first branched polymer specieshaving more arms with reactive electron pair accepting sites compared toa second polymer species carrying the nucleophilic moiety.

2. PEG-containing Biocompatible Layer

In some embodiments, the polymers in the biocompatible layer comprisepolyethylene glycol (PEG). The PEG may include species that have amolecular weight of between about 1 kDa and about 40 kDa. In particularembodiments, the PEG species have a molecular weight of between about 5kDa and about 30 kDa. In some embodiments, the biocompatible polymerpopulation consists of a species of polyethylene glycol (PEG). In othervariations, the weight average molecular weight M_(w) of the PEG polymerhaving at least one amino or carboxyl or thiol or vinyl sulfone oracrylate moiety (as a biocompatibleity-enhancing agent) can be fromabout 500 to about 1,000,000, or from about 1,000 to about 500,000. Inother embodiments, the biocompatible polymer population comprisesdifferent species of PEG.

In some cases, the polymer includes subunits of PEG. In some variations,the subunits of the polymers of the PEG-containing layer of the medicaldevice are or at least about 50%, or at least about 75%, at least about90%, or at least about 96%, or at least about 97%, or at least about98%, or at least about 99% or at least about 99.5% water.

In some cases, the water content of the PEG-containing biocompatiblelayer is between about 59% and about 98% water by weight. In otherembodiments, the biocompatible layer includes between about 50% andabout 75% water by weight. In other embodiments, the biocompatible layerincludes between about 75% and about 95% water by weight. In otherembodiments, the biocompatible layer includes between about 85% andabout 95% water by weight.

The PEG-containing biocompatible layer may include a PEG hydrogel havinga swelling ratio. To determine swelling ratio, the PEG-hydrogel can beweighed immediately following polymerization and then immersed indistilled water for a period of time. The swollen PEG hydrogel isweighed again to determine the amount of water absorbed into the polymernetwork to determine the swelling ratio. The mass fold increase an alsobe determined based on this comparison before and after water swelling.In some embodiments, the PEG-containing layer has a mass fold increaseof less than about 10%, or of less than about 8%, or of less than about6%, or of less than about 5%, or of less than about 4%, or of less thanabout 3%, or of less than about 2%, or of less than about 1%. In somecases, the mass fold increase is measured by weighing the hydrogel whenwet and then dehydrating it and weighing it again. The mass foldincrease is then the swollen weight minus the dry weight divided by theswollen weight. For the biocompatible layer as opposed to a bulkhydrogel, this could be accomplished by coating a non-hydrated substrateand then performing mass change calculations.

In another aspect, the invention provides for a biocompatible layer withtwo cross-linkable PEG species. The first PEG species may include areactive functional group adapted to react to another reactivefunctional on the second species comprising PEG or PAM. Any of thedescribed functional groups (e.g. previous section (A)(1)) may besuitable for forming a cross-linkage between the first and secondpolymer species.

In some cases, the first PEG species includes an electron pair acceptingmoiety and the second polymer species may include a reactivenucleophilic moiety. Once cross-linked through a reaction between theelectron pair accepting and nucleophilic moieties, the PEG polymernetwork forms a hydrogel with a water content or concentration. The PEGhydrogel may serve as the biocompatible coating a medical device toprovide improved wettability, lubricity, protein resistance, orantithrombogenicity.

3. Active Agents

The biocompatible polymer layer may include one or more active agents.Examples of active agents include one or more of a medicinal agent,UV-absorbing agent, a visibility tinting agent, an antimicrobial agent,an antithrombotic agent, a bioactive agent, a leachable lubricant, aleachable tear-stabilizing agent, or any mixture thereof. Additionalexamples of active agents includes a bioactive agent or drug,nanoparticle, cell, solute, or protein. The substances and materials maybe deposited on the medical device to augment the interaction of adevice with the body. These substances may consist of polymers, drugs,or any other suitable substance and may be used to treat a variety ofpathologies including but not limited dry eye disease, glaucoma, maculardegeneration, cardiovascular disease, thrombosis, renal failure,infection, wounds, cancer, or allergies.

Other examples of active agents include antimicrobial agents. Oneexample of an antimicrobial agent is silver nanoparticles.

4. Interpenetration Polymer Network

The outer hydrogel network may also consist of interpenetrating polymernetworks (or semi-interpenetrating polymer networks) formed in eithersimultaneous or sequential polymerization steps. For example, uponforming the initial outer hydrogel layer, the layer can be swollen in amonomer solution such as acrylic acid along with a crosslinker andinitiator. Upon exposure to UV light, a second interpenetrating networkwill form. The double network confers additional mechanical strength anddurability while maintaining high water content and highbiocompatibility.

B. Medical Devices

Many devices would benefit from a biocompatible coating including anydevice that is placed inside of or in contact with the body or any ofits tissues or fluids. The devices can be placed inside of the bodytemporarily during a medical procedure or can be implanted inside thebody for short term or long term use.

In some embodiments, the device is a catheter, defined as an artificialtube designed to carry fluid or serve as a conduit for instrumentation.This includes but is not limited to, catheters placed in arteries orveins for infusing or removing fluids such as saline or blood as fordialysis. Other embodiments include catheters placed in the peritonealcavity, urinary bladder, or skull. For example, an outer surface of acatheter could be coated and/or an inner surface of the catheter tubecould be coated.

Additional embodiments include trocars and endoscopes placed in theperitoneal cavity, urinary bladder, or skull. In some embodiments themedical devices include a laparoscope or laparoscopic tools. Furtherembodiments include tubing for instilling fluid and blood for tubing forcardiac bypass.

In some embodiments, the device is an implantable device placed in theskin, subcutaneous tissue, abdomen, spine, chest, brain or other bodilycavity, to detect, transmit, or record data, deliver a bioactivesubstance such as a drug, or deliver an electrical stimulus. The devicecan be placed inside of the body for short term use or for longer termuse. This includes but is not limited to, glucose sensors, endoscopiccameras, vital sign monitors, drug depot devices, neurostimulators,ultrasounds, breast implants, silicone implants, saline implants, herniameshes, penile implants, orthopedic rods, plates, pins or nails,pacemakers, cardiac valves, ear tubes, aneurysm coils, or intraocularlenses.

In some embodiments, the device is a stent designed to keep a cavityopen, including blood vessels, bile ducts, intestines, nasal passage orcavity, sinus cavity, or intraocular channels.

The hydrogel layer can be designed to increase biocompatibility of themedical device. In one example, the hydrophilic layer could reducethrombosis associated with a stent. In another example, the hydrophiliclayer could be designed to increase blood flow through a catheter orother device. In yet another example, the hydrophilic layer could reducea mammalian immune system response against the implanted device.

In some embodiments, the medical device is configured to be usedexternally on a mammalian body. Examples include a bandage, wounddressing, external sensor, hearing aid, or artificial skin.

In some embodiments the medical device can be a test strip. Examples oftest strips include drug, salivary, urine, blood, and semen test strips.

In some embodiments the medical device is not a contact lens.

In some embodiments the properties of the hydrogel layer can be selectedto meet desired optical characteristics. For example, the hydrogel layercan be substantially optically clear or the hydrogel layer and devicecan be substantially optically clear. In some embodiments the hydrogellayer is adapted to allow optical transmission through the hydrogellayer to the device.

In some embodiments the properties of the hydrogel layer can be selectedor modified to attenuate x-ray transmissions.

In some embodiments the hydrogel layer is adapted to enable diffusion ofbiologic molecules, glucose, solutes, polymers, or drugs.

In some embodiments the hydrogel layer has a lower coefficient offriction than the underlying device surface.

In some embodiments the hydrogel layer has a relative protein resistancecompared to the underlying device surface.

C. Attachment of Biocompatible Layer to Device

Another aspect of the invention provides for a coated medical devicewith biocompatible polymer layer that is covalently linked and attachedto the device. The covalent linkage between the biocompatible layer andthe outer surface of the medical device may be understood to be alinking moiety that is covalently disposed between the outer surface ofthe medical device and the biocompatible layer. In some cases, thelinking moiety covalently attaches the biocompatible layer to an outersurface of the device.

The coatings disclosed herein can be applied to a variety of differentmaterials. Examples of the outer surface materials list include: glass,plastic, titanium, stainless steel, nitinol, polyethylene,polypropylene, polyvinyl chloride, polytetraflouroethylene,polydimethylsiloxane, polyethylene terephthalate, polyamides, polyetherurethane, polyether urethane urea, polystyrene, polycarbonate,polysulfones, polymethyl methacrylate, poly 2-hydroxyethylmethacrylate,polyvinylalcohol, polyglycolic acid, polycaprolactone, polylactic acid,polyortho ester, cellulose acetate, collagen, or silk. The outer surfaceof the device can comprise a portion with one or more of thesematerials. In some embodiments the outer surface of the medical devicecan consist essentially of one or more of these materials.

In some embodiments, the linking moiety may include any of the reactivefunctional groups described in at least section (A)(1). In furthervariations, the linking moiety may be a resultant moiety formed from areaction between one or more of the reactive functional groups describedin at least section (A)(1). For example, the linking moiety may includean electron pair accepting group such as a Michael-type Michael-Typeelectron pair accepter (e.g. sulfone group) on a polymer species in thebiocompatible layer that reacts to covalently attach the biocompatiblepolymer layer to the device.

Advantageously, the biocompatible polymer layer may be attached to thedevice through similar reactions utilized to cross-link thebiocompatible polymer layer. Referring to FIGS. 5A-5C, the biocompatiblepolymer layer includes a first polymer species P1 having a reactivegroup A and second polymer species P2 with a reactive group N1. Asdescribed earlier, the biocompatible polymer layer may be formed bycross-linking the first polymer species and the second polymer speciesthrough a reaction between reactive group A and N1. FIG. 5A illustratesforming a biocompatible layer 70A/70B on an anterior surface 64 and aposterior surface 62 of a medical device 60. As shown in FIG. 5Across-linkages 63 covalently link the first and second species to formthe first biocompatible polymer layer 70A on the anterior surface 64 andthe second biocompatible polymer layer 70B on the posterior surface 62of the device 60.

Referring still to FIG. 5A, the first polymer species also forms acovalent linkage 61 with the outer surface of the device. As shown, thecovalent linkage is formed through the reactive group A of the firstpolymer species P1 and the device surface. In some embodiments, thereactive group A on the first polymer species P1 reacts to (1) crosslinkthe polymer species in the biocompatible polymer layer and (2) attachthe formed biocompatible polymer layer to the device. In such cases,this permits a first portion of the A moieties to react with the N1moieties and a second portion of A moieties to react with the devicesurface. In some cases, the concentration of the first polymer speciesP1 and/or the number of available reactive A moieties of the firstpolymer species exceeds the corresponding concentration of the secondpolymer species and/or available reactive N1 moieties.

Referring to FIG. 5B, the device may include a reactive moiety N2.Reactive moiety N2 may be adapted to react with reactive groups ofpolymer species in the biocompatible polymer layer. In some cases, thereactive moiety N2 only reacts to one of the polymer species. Referringto FIG. 5C, reactive moiety N2 reacts with reactive group A on the firstspecies P1 to form a covalent attachment between the biocompatiblepolymer layer and the device.

As can be appreciated, the reaction for attaching the biocompatiblepolymer layer to the device may include any number of suitable methodsknown in the art including those described in at least section (A)(1).In some cases, covalent linking occurs through nucleophilic conjugatereaction, Michael-type reaction (e.g. 1,4 addition), and/or Clickreaction between respective reactive groups on more than one polymerspecies in the biocompatible layer.

In some cases, the reactive A group is an electron pair acceptor and thereactive groups N1 and N2 are reactive nucleophilic groups. N1 and N2may be the same or different reactive groups. Continuing with theexample shown in FIGS. 5A-5C, the biocompatible polymer layer is formedby a first reaction between the reactive A group and reactivenucleophile N1. Additionally, the biocompatible polymer layer iscovalently attached to the core through a second reaction between thereactive A group and nucleophile N2. The two reactions may occursimultaneously or near simultaneously in the same reaction vessel.

Where the reactive functional groups include thiol and sulfonylmoieties, the reactive A group may be a sulfonyl group on a first PEGmacromer. The sulfone moiety functions as an electron pair acceptingmoiety on the first PEG macromer. The reactive nucleophiles N1 and/or N2may be a thiol group (see FIG. 4A). For the first reaction, the firstand second macromers form a cross-link through the reactive thiol andsulfonyl groups, which can results in a thioether moiety (see FIG. 4B).Where the N2 nucleophile on the device is also thiol, a thioether mayalso be formed by a reaction between the sulfonyl moiety on the firstPEG macromer and the N2 on the surface of the device.

As can be appreciated, the nucleophilic group (or other type of reactivegroup) on the device does not need to be the same as the reactive groupsin the biocompatible polymer layers. However, utilizing the samereactive groups may provide some advantages such as controllability andpredictability of the respective reactions.

In other variations, the biocompatible polymer layer are covalentlylinked to the device surface through a sulfonyl moiety such as, but notlimited to, an alkylene sulfonyl moiety, a dialkylene sulfonyl moiety,an ethylene sulfonyl moiety, or a diethylene sulfonyl moiety. In furthervariations, the biocompatible polymer layer is covalently attached tothe device through a sulfonyl moiety and a thioether moiety, or analkylene sulfonyl moiety and a thioether moiety, or a dialkylenesulfonyl moiety and a thioether moiety, or an ethylene sulfonyl moietyand a thioether moiety, or a diethylene sulfonyl moiety and a thioethermoiety.

In further variations, the biocompatible polymer layer is covalentlyattached to the device through an ester moiety, or alkylene estermoiety, or an ethylene ester moiety, or a thioether moiety, or an estermoiety and a thioether moiety, or an alkylene ester moiety and athioether moiety, or an ethylene ester moiety and a thioether moiety.

In further embodiments, the linkage between the device and thebiocompatible layer is covalent, to the particular exclusion of anyother form of chemical bond or association. For example, a hydrogellayer as described may be bound to the surface of a device by a chemicalbond that consists of a covalent bond.

E. Contact Angle

Advantageously, some of the contemplated coated devices provide for abiocompatible polymer layer that has a population of hydrophilicpolymers that are cross-linked with each other and, moreover, are as awhole, covalently attached to a device or layer. As such, thebiocompatible polymer layer can improve the hydrophilicity of thedevice.

As described in further detail below, the hydrophilicity or wettabilityof the hydrogel layer may be measured by a contact angle goniometer thatimplements a method known as a captive bubble contact angle test.Relatively high hydrophilicity is associated with a relatively lowadvancing contact angle.

In typical embodiments of the device according to the disclosedtechnology, when the device is subjected to a bubble contact angle test,the medical device shows an advancing contact in the range about 20° toabout 75°. In more particular embodiments, the medical device shows anadvancing contact in the range about 35° to about 55°.

FIGS. 6A-6C show aspects of a captive bubble test that is commonly usedin the device industry as a surrogate measure of wettability orhydrophilicity of surfaces, as provided by embodiments of thetechnology. FIG. 6A shows the setup 100 for a captive bubble test. Thesetup 100 includes a device holding fixture 102 in communication with atest device 104. An air bubble 106 is positioned at a surface of thetest device from a syringe pump 108. The test device 104 is illustratedwith a curved surface; however, devices having different geometries canalso be tested.

FIG. 6B shows a schematic view of the contact angle as it occurs in anaqueous solution between the surface of a device and an air bubble, asthe air bubble is being inflated against or being withdrawn away fromthe device.

FIG. 6C provides a schematic series of angles created as a bubble isbeing inflated against the device, and then withdrawn. The left side ofthe drawing depicts the “receding phase” of the test; the right side ofthe drawing depicts the “advancing phase of the test. On the left, afterthe bubble first makes contact at what will be the central contact pointbetween the bubble and the device, the area of mutual contact expands,and the surrounding aqueous space recedes from the central contactpoint. Accordingly, this is termed the “receding phase”. On the right,as the bubble is being withdrawn, the aqueous solution advances towardthe central point of contact between the bubble and the device.Accordingly, this is termed the “advancing phase” of the test. Theseprofiles can be videographed during the test to capture the dynamics. Inthe recorded videos, software-based edge detection and angularseparation techniques can be used to measure the receding and advancingangles at the interface of the bubble and device.

In both the advancing and receding portions of the test, a small anglereflects the relatively high affinity of the device surface for water,rather than air. Thus, there is an association between a small contactangle and hydrophilicity or wettability of the device surface. Incontrast, a large contact angle reflects a relative lack of affinity ofthe device surface with water. By means of this test, the hydrophilicityof device embodiments of the technology may be quantified.

In an exemplary embodiment, the device having a biocompatible polymerlayer as described has an advancing contact angle of at least 20degrees, or at least 25 degrees, or at least 30 degrees, or at least 35degrees, or at least 40 degrees. In another embodiment, the advancingcontact angle is between about 20 degrees and about 40 degrees, orbetween about 20 degrees and about 35 degrees, or between about 20degrees and about 30 degrees, or between about 20 degrees and about 25degrees, or between about 25 degrees and about 40 degrees, or betweenabout 25 degrees and about 35 degrees, or between about 25 degrees andabout 30 degrees, or between about 30 degrees and about 40 degrees orbetween about 35 and about 40 degrees. In another variation, theadvancing contact angle is at least about 8 degrees, or at least about 9degrees, or at least about 10 degrees, or at least about 11 degrees, orat least about 12 degrees, or at least about 13 degrees. In an exemplaryembodiment, the advancing contact angle is between about 8 degrees andabout 20 degrees, or between about 8 degrees and about 17 degrees, orbetween about 8 degrees and about 14 degrees, between about 8 degreesand about 12 degrees, or between about 9 degrees and about 20 degrees,or between about 9 degrees and about 17 degrees, or between about 9degrees and about 14 degrees, between about 9 degrees and about 12degrees, or between about 10 degrees and about 20 degrees, or betweenabout 10 degrees and about 17 degrees, or between about 10 degrees andabout 14 degrees, between about 10 degrees and about 12 degrees, orbetween about 11 degrees and about 20 degrees, or between about 11degrees and about 17 degrees, or between about 11 degrees and about 14degrees.

FIG. 15 shows contact angles measured for contemplated embodimentsdescribed. Lot numbers are shown for the measured embodiments made fromdescribed methods.

F. Methods of Making a Coated Device or Multi-Layered Device

Another aspect of the invention provides for methods of making describedcoated and/or layered devices.

In some embodiments, the method includes the steps of reacting a surfaceof a device with a biocompatible polymer solution. The biocompatiblepolymer solution may contain one or more subpopulations or species thatare adapted to react to form a coating on at least a portion of thedevice. In some cases, the biocompatible polymer solution reacts to forma cross-linked coating on the device. The coating may be partially orsubstantially completely cross-linked.

As shown in FIG. 3A, the biocompatible polymer solution may include afirst polymer species with a reactive group A and a second polymerspecies with a reactive group N. The biocompatible polymer layer may beformed on the medical device surface by reacting the reactive groups onthe first and second polymer species to form the cross-linkedbiocompatible polymer layer. As shown in FIG. 3B, the reactive groups Aand N may form a covalent linkage 54 between the first and secondpolymer species to thereby cross-link the two species and result in abiocompatible polymer layer. In some cases, the reaction between thefirst and second reactive groups on respective polymer species forms ahydrogel.

As described, any suitable reaction may be employed to form thebiocompatible polymer layer. These include (without limitation)nucleophilic conjugate reactions, Michael-type reactions (e.g. 1,4nucleophilic addition reactions), and/or click reactions. In some cases,the reactive groups A and N are an electron pair accepting moiety and anucleophilic moiety respectively.

Additionally, in some variations, the polymer species or subpopulationwith in the biocompatible polymer layer may include PEG species. In somecases, a first PEG species reacts with a second polymer species, such asa PEG or PAM species, to form the biocompatible polymer layer. Forexample, the first PEG species may include an electron pair acceptoradapted to react to a nucleophilic reactive moiety of a second PEGspecies or PAM species to covalently link the polymer species.

Some embodiments provide for a covalent attachment between thebiocompatible polymer layer and the device. For example, one or more ofthe polymer subpopulation or species within the biocompatible polymerlayer or solution may be adapted to react to the device to form acovalent attachment between the biocompatible layer and the device. Insome cases, the method of biocompatible polymer layer attachmentincludes the step of reacting at least one of the polymer species withreactive sites on the surface of the device to form covalent bondsbetween the polymer species and the device surface.

In some embodiments modifying the outer surface of the device includesone or more of: pH adjustment, plasma activation, light activation,activation of the liquid monomer mix, wet activation, and adding amonomer that reacts with the outer surface of the device that stillleaves reactive sites.

Referring again to FIGS. 5A-5C, a first polymer species P1 may include areactive group A that is adapted to react to a reactive group N2 of thedevice 60 surface. The reaction between the A and N2 groups results in acovalent linkage 61 between the first polymer species P1 and the device60. As shown, the reactive group A may also be adapted to react withanother reactive moiety N1 of a second polymer species P2 to form thebiocompatible polymer layer. As such, a first reaction between P1 and P2forms the biocompatible polymer layer and a second reaction couples thebiocompatible polymer layer to the device.

In some cases, the same reactive group A on the first polymer species P1is capable of reacting to either the reactive moiety N1 or N2. In onevariation, a first portion of the reactive A groups react to the N1moiety and a second portion of the reactive groups react to the N2moiety. In some embodiments, the first and second portions of thereactive A groups are on the same molecule of a polymer species. Infurther variations, the first and second portions of the reactive Agroups are on different branch arms of the same polymer species. Thedual reactions between P1 and P2, and P1 and core may occur in the samereactive vessel and during the same reaction time (or overlapping insome portion of the reaction time).

As described, any suitable reaction may be employed to form thebiocompatible polymer layer and attach the biocompatible polymer layerto the medical device. These include (without limitation) nucleophilicconjugate reactions, Michael-type reactions (e.g. 1,4 nucleophilicaddition reactions), and/or click reactions. For example, the pluralityof reactions may all be nucleophilic conjugate reactions. Alternatively,the plurality of reactions may be different types of reactions.

In some embodiments, the first and second reactions are nucleophilicconjugate reactions, more particularly, both are 1,4-nucleophilicaddition Michael-type reactions. By way of example, in some embodiments,the nucleophilic reactive moiety of the first macromer populationcomprises a thiol group and the electron pair accepting moiety of thesecond macromer population comprises a sulfone group.

In other embodiments of the method the first and second nucleophilicconjugate reactions may be described more broadly as a “Click” typereaction. Click reactions, as originally described by Karl Sharpless andothers, refer to modular assembly of macromolecules that are typified asoccurring in an aqueous environment, delivering high yield as a resultof being driven to completion by large thermodynamic force, and creatingsubstantially no byproducts, or byproducts that are non-toxic tobiological systems. The click reactions are advantageous for applicationtoward the manufacture of devices because the devices may be reacted inan aqueous solution, without toxic byproducts, rapidly, and with a highyield.

Other examples of click type reactions that could be used to attachbranched polymers in our immersive dip coating process including (a)general thiol-ene click reactions in general, (b) [3+2] cycloadditions,including the Huisgen 1,2-dipolar cycloaddition, (c) Diels-Alderreaction, (d) [4+1] cycloadditions between isonitriles (isocyanides) andtetrazines, (e) nucleophilic substitution especially to small strainedrings like epoxy and aziridine compounds, (f) carbonyl-chemistry-likeformation of ureas, and (g) addition reactions to carbon-carbon doublebonds, such as involve dihydroxylation or the alkynes in the thiolynereaction.

In a particular embodiment, the method of making the described coateddevice includes the steps of reacting an outer surface of the devicewith a first PEG species of a biocompatible polymer solution, whereinthe first PEG species comprises an electron pair accepting moiety and afirst portion of the electron pair accepting moiety forms a covalentattachment to the outer surface of the device through a firstnucleophilic conjugate reaction; and reacting the first PEG species ofthe biocompatible polymer solution with a second polymer species of thebiocompatible polymer solution, the second polymer species comprising anucleophilic reactive moiety adapted to covalently link to a secondportion of the electron pair accepting moiety of the first PEG speciesin a second nucleophilic conjugate reaction to thereby at leastpartially cross-link the first and second species, wherein a hydrogelcoating is formed and covalently attached to the outer surface of thedevice by the first and second nucleophilic conjugate reactions.

In additionally embodiments, the method includes activating a surface ofthe device. Activating the surface may form a plurality of chemicallyreactive sites on the surface. The reactive sites may be, for example,nucleophilic sites for reaction with a biocompatible polymer.

Referring to FIG. 7, a surface 160 of a medical device without reactivesites is shown with a plurality of reactive sites 162 following anactivation or modification process. In some cases, a plasma process isused to activate the surface of a device. The activation process mayinclude the step of exposing the outer surface of the device to gasplasma. In some embodiments, the device is transferred to a holdingdevice, typically metal, and placed in a vacuum plasma chamber. Thedevice is plasma treated in an atmospheric plasma to form reactive siteson the surface. In some cases, atmospheric plasma is applied to thedevice at 200 mTorr for about 3 minutes to thereby result innucleophilic functional sites on the device. In some embodiments, thedevices are dehydrated prior to the plasma treatment.

In further variations, the device surface may be activated throughplasma treatment, preferably in oxygen or nitrogen gas. For example, thecontemplated process may include activating a core material in anitrogen plasma. In other variations, the surface may be activatedthrough a plasma treatment in carbon dioxide, carbon monoxide, argon,nitrous oxide, hydrogen, or air.

In some embodiments modifying an outer surface of the device forms aplurality of reactive nucleophilic sites or a plurality of electrophilicsites on the outer surface.

In some embodiments modifying any other surface of the medical devicecan be done by adding a bifunctional monomer or a polymer to aprepolymerization mixture used to form a portion of the medical device.The bifunctional monomer or polymer does not substantially change themechanical properties of the contact lens. The bifunctional monomer orpolymer provides additional nucleophilic or electrophilic reactive siteson the surface of the medical device.

In some embodiments modifying the outer surface of the medical deviceincludes adding a monomer that reacts with the medical device surfacebut still leaves reactive sites after the reaction.

In other embodiments, activation of the device surface can also occurthrough exposure to increasing pH's, for example solution pH of above11.

In further embodiments, activation can also occur by modifying themonomer mix to include groups that are reactive to the branchedbiocompatible coating polymers. Activation of the monomer mix can be adirect activation, or activation with a protected group that is cleaved,for example by light or changing pH. In other cases, plasmapolymerization of functional silanes including mercapto and aminosilanes may be used for activation. Additionally, plasma polymerizationof allyl alcohol and allyl amine can also be used for activation.

In some embodiments, the device activation or modification step resultsin a reactive group N2 (shown in FIG. 5B) that is capable of reactingwith at least one of the polymer species of the biocompatible polymerlayer. In some cases, at least one of the polymer species in thebiocompatible polymer layer reacts with a portion of the plurality ofreactive sites on the device outer surface to form a covalent attachmentbetween the biocompatible polymer layer and the device surface. In somecases, the device is activated prior to the formation of thebiocompatible polymer layer on the device surface.

In some embodiments, the process of making the coated device includesthe step of reacting the activated device surface with a population offunctionalized biocompatible polymers. For example, the biocompatiblepolymers may include a population of functionalized branchedbiocompatible macromers with a first subpopulation functionalized with anucleophilic reactive moiety and a second subpopulation functionalizedwith an electron pair accepting moiety. In further embodiments, themethod may include reacting the functional moieties of two macromersubpopulations with each other in a first nucleophilic conjugatereaction to form covalent linkages between the two macromersubpopulations, thereby forming a cross-linked polymer network.

The method may also include reacting the electron pair acceptingmoieties of second macromer subpopulation and the nucleophilic moietiesof the activated device surface in a second nucleophilic conjugatereaction to covalently attach the electron pair accepting moieties tothe device surface. The first and second nucleophilic conjugatereactions, when complete, yield a device with a cross-linkedbiocompatible hydrogel layer covalently attached thereto.

As described, the first and second nucleophilic conjugate reactions maybe of the same type with the reactions differing by having differentreactants. The two reactions may involve the same electron pairacceptor, such as the biocompatible polymer species comprising anelectron pair accepter that can participate in a plurality of reactions.The plurality of reactions may differ by having distinctnucleophilically-reactive parent molecules, in one case, a biocompatiblepolymer species with a nucleophilic moiety, and in the second case, adevice surface with a nucleophilic moiety.

Referring to FIG. 8, a schematic diagram 200 of two exemplary conjugateaddition reactions 214, 216 and the principal reactants are shown. Theprincipal reactants can be understood as nucleophilic moieties 202 andelectron pair accepting moieties 204. In a first reaction, a reactanthaving nucleophilic functional moiety, such as PEG-thiol 206, reactswith a reactant having an electron pair accepting functional moiety 204,such as PEG-sulfone 204; the product of the reaction 214 is a linkedpair of PEG molecules, linked by way of a central thioether bond. As thereaction proceeds among the functionalized PEG molecules, the PEG takesthe form of a linked network, and inasmuch as a PEG network isbiocompatible, in an aqueous environment, the network takes the form ofan integrated hydrogel.

In a second reaction 216, a reactant 204 having an electron pairaccepting functional moiety, such as PEG-sulfone 204, reacts with anucleophilic site on the surface of the medical device 210; the productof this second reaction 216 is a covalent bond between the PEG-sulfoneand the device. As above, inasmuch as the individual molecular thatcovalently link to the activated device surface also are included as aconstituent of a hydrogel structure, the hydrogel structure, as a whole,becomes covalently linked to the device.

FIG. 9A-9D show more detailed and particular aspects of reactants andreactions, as depicted schematically in FIG. 8. FIG. 9A shows a devicesurface being activated by a plasma treatment to yield a device surfacecovered with a bed of activated nucleophilic sites. FIG. 9B shows thestructure of examples of reactants, including a PEG molecule, aMichael-Type electron acceptor such as a vinyl sulfone moiety, anucleophile functional group such as a thiol, and the detail of theMichael type reaction itself.

FIGS. 9C-9D show a reaction process whereby two subpopulations ofbranched biocompatible polymer species, a first subpopulation with anucleophile functionality (N) and a second subpopulation with anelectron pair accepting functionality (A) are in a reaction solutionthat bathes a nucleophilically activated (N) device. In the lowerportion of FIG. 9D, per the first reaction as depicted in FIG. 8,reaction individual members of the two subpopulations have begun to linktogether by way of their functional groups, to form a hydrogel network.And, per the second reaction as depicted in FIG. 8, electron pairaccepting moieties (A) of biocompatible polymers engage in covalentlinking with the nucleophilic sites on the device surface, therebycovalently attaching the hydrogel network to the device surface.

FIGS. 10A-10B provide flow diagrams of two variations of processes formaking a device with a covalently attached hydrogel membrane. FIG. 10Ashows a process that includes a plasma activation method. Such plasmatreatment may include exposure to any of an oxygen plasma or a nitrogenplasma. FIG. 10B shows a process that includes a chemical or “wet”activation method.

As described in FIG. 10A, a medical device surface 320 is plasma treated322 to form a plurality of reactive sites on the device surface. Thismay be accomplished by placing the device into a vacuum plasma chamber.In some embodiments, the device is transferred to a holding device,typically metal, and placed in a vacuum plasma chamber.

Referring still to FIG. 10A, after the device surface is activated, theactivated device is placed into a solution that includes coating polymerand/or coating polymer species or precursors 324. The coating polymermay be any of the described biocompatible polymers described including abiocompatible polymer population including subpopulations offunctionalized branched PEG species. In some cases, the solution alsoincludes isopropyl alcohol and water. The solution may have a pH >7. Thesolution may be agitated to create a well-stirred bath and the devicesincubate in the solution for some period of time. In some cases, theincubation time is about 50 minutes.

Optionally, the coating process may include extraction steps to removean unwanted component from the device. For example, where asilicone-based lens core is used for a base or substrate, unreactedsilicone molecules in the lens cores are extracted or diffused out ofthe devices. Advantageously, the extraction process removes raw corematerial (e.g. raw silicone for a silicone-containing core) that mayleach out of the device into the body tissues. As such, further steps ofthe process may include transferring the device to a solution ofisopropyl alcohol and water for a period of time such as about 50minutes 326 to continue extracting unreacted silicone molecules from thedevices. Additionally, as a second rinse 328, the device may betransferred to a fresh solution of isopropyl alcohol and water for aperiod of time such as about 50 minutes to further extract unreactedsilicone molecules from the devices. In some variations, the devices mayalso be transferred into a water bath 330 to equilibrate in water for aperiod of time (e.g. about 50 minutes).

Additionally, as shown in FIG. 10A, the devices may be transferred to apackaging container with a packaging solution 332. The devices may alsobe autoclaved 334. In some cases, the device is autoclaved at about 250°F. for about 30 minutes.

FIG. 10B describes a wet-activation process for activating a device andcoating the activated device. The process may begin with a medicaldevice in a hydrated state 370. The next step may include activating thehydrated device 372. This may be accomplished by a plasma or chemicaltreatment. For example, ozone may be used to activate the devicesurface. Once activated, the activated device may be placed into asolution containing the coating material 374. The solution may include abiocompatible polymer solution as described and water. In some cases,the solution is at a pH >7. The solution may be agitated to create awell-stirred bath and the device incubates therein. In some cases, thedevice incubates for about 50 minutes.

Next, the device may be transferred to a water bath to equilibrate inwater 376. The equilibration step may also serve to wash excess polymerfrom the device. The device may be equilibrated in water for about 50minutes. The device may be transferred to a packaging container withpackaging solution 378. Additionally, as another step, the device may beautoclaved. In some cases, the device is autoclaved at about 250° F. forabout 30 minutes. After the autoclave step, the resulting coated deviceis ready for use 382.

Advantageously, the methods described herein provide for acost-effective coating process that can be integrated with devicemanufacturing processes currently employed in the industry.

Some embodiments of the method may be understood as an immersive method,wherein activated device are immersed in a reaction solution within astirred vessel, the solution including biocompatible macromer reactants,and the reaction vessel operated to achieve appropriate reactionconditions. The reaction vessel and aspects of the conditions, inbiochemical engineering terms, may be understood as occurring in acontinuously stirred reaction tank (CSTR). In typical embodiments, thereacting steps occur within a reaction solution that has an aqueoussolvent. Such the aqueous solvent may include any one or more of water,methanol, ethanol, or any suitable aqueous solvent that solubilizes PEG.

FIG. 11A provides a schematic view of a continuously stirred tankreactor (CSTR) 400 suitable for performing the reaction described. TheCSTR 400 includes an agitator 402 for stirring the reaction contentswithin the tank. A feeding line or conduit allows input or inflow 406 ofreaction solutions including a biocompatible polymer solution containingat least one polymer species. As shown, first and second polymer speciesflow into the CSTR 400. In some cases, the first and second polymerspecies have different flow rates VP1 and VP2 respectively. In othercases, the flow rates may be the same.

FIG. 11A shows a plurality of implantable medical devices, such assensors 404 a and 404 b in the CSTR 400. In some cases, the implantablemedical devices may be held in a mesh holder with openings or sufficientporosity to allow contact between the held implantable medical devicesand the solution in the CSTR. The skilled artisan would appreciate thatdifferent tank geometries can be used based on the size and shape of themedical device to be coated.

FIG. 11A also shows an output or outflow opening or conduit 408 forremoving fluid from the CSTR 400. In some cases, the removed fluid isspent reaction fluid. The flow rate of the removed fluid may be designedas V₀.

In some cases, T_(p) indicates the polymer residence time and T_(C)indicates the contact residence time in the CSTR 400. FIG. 11B shows therelationship between polymer coating particle size as a function of timein a CSTR 400 where T_(p) is 1-72 hours and T_(C) is 0.25-24 hours.

In some variations, within the reaction solution, the totalbiocompatible macromer concentration in the solution typically rangesbetween about 0.01 (w/v) % and about 0.50 (w/v) %. In some embodiments,the first and second macromer subpopulations are present in the solutionat substantially equivalent concentrations. However, in otherembodiments, the concentration of the reactive moiety of the secondmacromer subpopulation (an electron pair accepter) exceeds theconcentration of the reactive moiety of first macromer subpopulation (anucleophile).

Having an excess of electron pair reactive moieties with respect to thenucleophilic reactive moieties can be advantageous for the reactionsincluded herein for the purpose of forming embodiments ofhydrogel-coated medical devices in that the electron pair acceptingmoieties of the biocompatible polymer subpopulation so-functionalizedcan participate in two reactions. The polymer subpopulationfunctionalized with the electron pair acceptors participates (1) incovalent cross linking with the subpopulation functionalized withnucleophiles and (2) covalent attachment to nucleophilic sites on themedical device surface. In contrast, the polymer subpopulationfunctionalized with a nucleophilic moiety engages only in the singlereaction wherein it engages the polymer subpopulation functionalizedwith the electron pair accepting moiety.

The reactant concentration may also be appropriately expressed in termsof the relative concentrations of the reactive moieties of theparticipant macromers, rather than the concentrations of the macromersthemselves. This follows from the possible variations in the degree towhich the macromers are decorated with the function moieties thatactually participate in the reactions. Accordingly, in some reactionembodiments, the concentration of the reactive moiety of the secondmacromer subpopulation exceeds the concentration of the reactive moietyof the first macromer subpopulation by at least about 1%. In moreparticular embodiments, the concentration of the reactive moiety of thesecond macromer subpopulation exceeds the concentration of the reactivemoiety of the first macromer subpopulation by an amount that rangesbetween about 1% and about 30%. And in still more particularembodiments, the concentration of the reactive moiety of the secondmacromer subpopulation exceeds the concentration of the reactive moietyof the first macromer subpopulation by an amount that ranges betweenabout 5% and about 20%.

Returning now to aspects of the reaction conditions, in someembodiments, the reacting steps are performed for a duration of betweenabout 5 minutes and about 24 hours. In particular embodiments, thereacting steps are performed for a duration of between about 0.5 hourand about 2 hrs. In some embodiments, the reacting steps are performedat a temperature at a range between about 15° C. and about 100° C. Inmore particular embodiments, the reacting steps are performed at atemperature at a range between about 20° C. and about 40° C. In someembodiments, the reacting steps are performed at a pH between about 7and about 11.

In some embodiments, the activated device is incubated in a dilutereaction solution containing 4-arm branched, 10 kDa PEG endfunctionalized with thiol groups, and 8-arm branched, 10 kDa PEG endfunctionalized with vinyl sulfone groups. The dilute solution containsbetween 0.01 and 0.5% total polymer, with a 10% excess of vinyl sulfonegroups. The reaction can be performed in aqueous conditions, methanol,ethanol, or other solvents in which PEG is soluble. The reaction can beperformed at a range of temperatures between about 15 degrees C. andabout 100 degrees C. The reaction can be performed at a range oftemperatures between about 20 degrees C. and about 40 degrees C. Thereaction can be performed from between about 5 minutes and about 24hours. The reaction can be performed at basic pH's, preferably in therange of about 5 to about 11. The reaction can be performed at basicpH's, preferably in the range of about 7 to about 11.

As polymer reaction proceeds in the dilute solution, hydrogels (e.g.cross-linked biocompatible polymer particles) are formed as branchedpolymers react with each other. Reaction progress can be monitored usingdynamic light scattering techniques to measure hydrogel particle sizeand/or macromer aggregation level as the hydrogel network is forming.Temperature, pH, convection speed, and concentration will influencereaction rate and hydrogel particle size and formation rate. Hydrogelparticles that are smaller than visible light will not cause opticaldistortions in the device. Layer thickness can be regulated bymonitoring hydrogel formation during the course of reaction.

In some variations, polyethylene glycol is the biocompatible polymer.However, other multifunctional natural and synthetic biocompatiblepolymers can also be used, for example poly(vinyl alcohol),poly(vinylpyrrolidinone), Poly(N-isopropylacrylamide) (PNIPAM) andPolyacrylamide (PAM), Poly(2-oxazoline) and Polyethylenimine (PEI),Poly(acrylic acid), Polymethacrylate and Other Acrylic Polymers,Polyelectrolytes, hyaluronic acid, chitosan, dextran.

In other embodiments, the methods include the step of forming across-linked biocompatible polymer layer on a device surface that iscovalently attached to the device. Covalent linkages between thebranched biocompatible polymers may occur due to Michael typenucleophilic conjugate addition reaction between vinyl sulfone and thioland covalent linkages between the biocompatible polymer and the devicesurface occur due to conjugate addition reaction between vinyl sulfoneand nucleophiles generated during the activation step. In some cases,reactivity of nucleophiles will increase with rising pH as molecules areincreasingly deprotonated.

In further variations, any general Michael type reaction betweenenolates and conjugated carbonyls can also be used. For example,acrylate, methacrylate, or maleimide can be substituted for vinylsulfone. Other examples include the Gilman reagent as an effectivenucleophile for addition to conjugated carbonyls. The stork enaminereaction can be performed using enamines and conjugated carbonyls.

Additional covalent reaction mechanisms include hydroxylamine reactionwith electrophiles such as aldehyde or ketone to produce oxime linkages.

Additional covalent reaction mechanisms include reaction ofN-Hydroxysuccinimidyl esters with amines.

Additional covalent reaction mechanisms include isocyanates reactionwith nucleophiles including alcohols and amines to form urethanelinkages.

In another embodiment, a PEG containing layer can be attached to adevice using cast molding techniques. First, the device is modified toensure surface groups are present that will react covalently with thePEG macromers. Second, molds are prepared that contain a top part and abottom part in the same or similar shape as the device. The device isplaced into the mold along with the liquid macromer PEG solution and themold halves are placed together. The PEG can cure thermally forapproximately 1 hour and the mold is taken apart.

The PEG containing layer can also be attached to the device using a dipcoating method. First, the device is modified to ensure surface groupsare present that will react covalently with the PEG macromers. Forexample, surface groups can be generated in a plasma treatment step, orby incubating in a basic solution, or by including reactive groups inthe monomer mix. Next, a dip coating solution is prepared that consistsof a dilute solution of reactive, branched, biocompatible polymers. Theactivated device is placed in the dip coating solution and incubated for1-24 hours. Following incubation, the device is rinsed thoroughly andthen autoclaved in an excess volume of buffer solution prior tomeasuring captive bubble contact angles.

In alternative method, the biocompatible polymer layer can be covalentlyattached to the device using another dip coating method. First, thedevice can be modified to create surface chemical moieties that arecovalently reactive to the biocompatible macromers. For example, surfacegroups can be generated in a plasma treatment step, or by incubating ina basic solution, or by including reactive groups in the monomer mix.Next, a dip coating solution can be prepared that consists of a dilutesolution of reactive, branched, biocompatible polymers. For example, thedilute solution can consist of a branched poly(ethylene glycol) endfunctionalized with vinyl sulfone and thiol in a solution containing0.2M triethanolamine. The activated device is placed in the dip coatingsolution and incubated for 1-24 hours at a temperature between about 20°C. and about 60° C. Following incubation, the device is rinsedthoroughly and then autoclaved in an excess volume of phosphate bufferedsaline.

In an exemplary embodiment, the invention provides a method of making adevice described herein. The method comprises contacting an activateddevice and a dip coating solution, thereby making a device. In anexemplary embodiment, the method further comprises activating a device,thereby creating an activated device. A device can be activated througha method known to one of skill in the art or a method described herein,such as plasma treatment or incubation in a basic solution, or byincluding reactive groups in the monomer mix. In an exemplaryembodiment, the contacting takes place for between 1-24 hours, or from1-12 hours, or from 12-24 hours, or from 6-18 hours. In an exemplaryembodiment, the method further comprises rising the device after thecontacting step. In an exemplary embodiment, the method furthercomprises autoclaving the device after the contacting step. In anexemplary embodiment, the method further comprises autoclaving thedevice after the rinsing step.

In another embodiment, an alternative method of forming a coated deviceincludes a spray coating approach wherein a reactive ultrasonic spraycoating is used to coat substrates with a thin, adhered layer ofcross-linked hydrogel. A two-component hydrogel, comprising branched PEGend-capped with vinyl sulfone, and branched PEG end-capped with thiol,was used to produce the cross-linked thin films. The two components aresimultaneously dripped onto an ultrasonic spray nozzle where they arecombined and atomized into small droplets, which then are accelerated tothe substrate in an air sheath. The rate of reaction is adjusted toensure that reaction is fast enough that a solid structure forms on thesurface, but slow enough that the components do not instantly polymerizeupon mixing at the nozzle.

An alternative spray method, considered appropriate for scaledmanufacturing, is ultrasonic spray coating, a technique that enablesprecise, thin film coatings. It has been employed previously for stentsand in the microelectronics industry, and is currently used in severalhigh volume manufacturing lines. A state of the art Sonotek instrumentwas used to form coated device prototypes. This technology enables 3Dprinting, thus potentially providing a platform for constructingcomplicated device structures with integrated sensors or electronics.

The Sonotek instrument has an ultrasonically driven spray nozzle withtwo feed lines that deposit solution onto the tip. A two-componenthydrogel system involves dissolving the PEG vinyl sulfone component inmethanol containing triethanolamine (TEOA; acting as an organic base)and the PEG thiol component in pure methanol. The two solutions aredelivered to the nozzle tip at a rate of 5 microliters per minute andthe concentration of each PEG component is adjusted such that equalvolumes of each component mix to achieve a 10% molar excess of vinylsulfone groups. When the solutions are deposited on the ultrasonic tip,they mix and are atomized into droplets that are approximately 20microns in diameter. A pressured air sheath then accelerates thedroplets onto the surface to be coated. By including FITC-malelimide inthe PEG vinyl sulfone component, mixing and crosslinking that result infilm deposition can be films. A concentration of TEOA and identifiedthat at a molar ratio of TEOA:SH of 6:1 could deposit a uniformcrosslinked hydrogel on a variety of device substrates. An alternativeaqueous spray coating method was also tested and was shown to befeasible, however for the device substrates, the methanol processadvantageously produces a highly uniform film of ˜5 microns. The contactangle measurements on coated devices demonstrated the integrity of thedeposited film.

FIGS. 12A and 12B depict alternative embodiments of methods of thetechnology that are directed toward making devices with a covalentlyattached bilateral hydrogel layer, in which the hydrogel layer sidesdiffer in composition or depth. In some instances, it may beadvantageous to produce a device surface that is asymmetric (convex sidevs. concave side) with regard to the thickness or composition of thehydrogel coating that is associated with the two surfaces, respectively.For example, it may be advantageous to form a hydrogel layer on theconcave (or posterior) device surface that is thicker than the layer onthe convex (or anterior) device surface.

FIG. 12A shows a method to produce a device with a thicker biocompatiblelayer on the concave surface 503 in which a device 500 containing a UVblocking agent is dipped into a non-mixed solution 502 of coatingpolymer, and then exposed to UV light 504. UV light accelerates thereaction between polymers as well as the reaction between polymer andsurface. The light strikes the device on a vector that is perpendicularto the device surface, directly onto the anterior side 503 and throughthe posterior side 501. Due to the UV blocking agent present in thedevice, the posterior side 503 is exposed to a higher dose of UV light,while the anterior side 501 receives a relatively lower dose. Thisasymmetric UV dosing creates layers of varying thickness. To achievecomplete independent variation in layer thickness control, light dosageof varying intensity can also be used to shine from each side.

FIG. 12B shows an alternative method for producing a thicker hydrogellayer on the concave surface 503 of the device 500. As shown, the convexsurface 501 of the device 500 is held in a vacuum chuck 506 whileexposing the concave surface 503 to the coating polymer 502. The vacuumsuction pulls the aqueous solvent through the device 500 whileconcentrating coating polymer at the device interface at the concavesurface 503. After achieving a desired layer thickness, the device 500is removed from the chuck 506. In some variations, the device 500 isthen placed into a well-mixed bath of coating polymer, to continuebuilding the hydrogel layer on both sides of the device.

G. Examples

Additional properties of the hydrogel coating and the processes forforming hydrogel coatings are illustrated in the Examples. The processesand properties of the coatings detailed in the Examples are detailed forcontact lenses; however, the coating properties and processes areapplicable to the additional medical devices disclosed herein. TheExamples are not intended to define or limit the scope of the invention.

Example 1

Functionalization of Silicone Hydrogel Lenses. Silicone hydrogel lenseswere stored in purified water prior to functionalization. A solution of10% by volume divinyl sulfone in 0.5M sodium bicarbonate (pH 11) wereprepared. Lenses were added to the solution at a ratio of 6 lenses per10 mL of solution and mixed vigorously on a shake plate for 60 minutes.The lenses were removed, washed in a strainer to remove any excessreaction solution, and added to a container of purified water at a ratioof 1 lens per 20 mL of water. They were mixed vigorously on a shakeplate for 60 minutes. The washing procedure was repeated twice more fora total of 3 washes. Next, the lenses were stored in triethanolamine(TEOA) for at least 20 minutes and up to 6 hours prior to attaching thehydrogel layer.

Example 2

Functionalization of Silicone Lenses. Silicone lenses were stored dryprior to functionalization. Lenses were added to a solution of 10%hydrochloric acid and 2% hydrogen peroxide at a ratio of 6 lenses per 10mL. The lenses were mixed vigorously for 5 minutes and then removed,washed in a plastic strainer to remove any excess reaction solution, andthen added to a container of purified water a ratio of 1 lens per 20 mLof water. They were mixed vigorously for 5 minutes. Next the lenses wereadded to a solution of 95% ethanol, 3% water, 1% glacial acetic acid,and 1% 3-mercaptopropyltrimethoxysilane and mixed vigorously for 60minutes. The lenses were rinsed in a strainer with pure ethanol andadded to a container of pure ethanol at a ratio of 1 lens per 20 mL ofethanol. The lenses were mixed vigorously for 60 minutes. This washingprocedure was repeated once more. Finally the lenses were removed fromthe rinse solution and allowed to dry. They were stored at 4° C. Priorto attaching hydrogel to the lenses, they were immersed in a solution of150 mM dithiothreitol for 30 minutes and then rinsed in DI water.Following this step, hydrogel must be attached within 15 minutes.

Example 3

Plasma Functionalization of Silicone Containing Layers. Siliconecontaining layers (silicone or silicone hydrogel) were placed in avacuum chamber for 2 hours to ensure all moisture was removed. Afterdrying, lenses were inserted into a plasma chamber. Pressure was reducedto 375 milliTorr with continuous flow of nitrogen gas at 10 standardcubic centimeters per minute. The chamber was allowed to stabilize for30 seconds before initiating plasma at 100 W for 3 minutes. The chamberwas then vented to atmosphere and lenses removed. Lenses were then usedwithin 1 hour.

Example 4

Preparation of molds for adding bulk layers to contact lenses. Moldswere prepared using silicone hydrogel lenses and agar. 5 grams of Agarwere dissolved in 333 mL of water and the solution was heated on atemperature controlled stirred plate until it reaches 88° C. A delrinplate containing small cavities (1″ in diameter and 0.5″ deep) was usedto contain each individual mold. Liquid agar is pipetted to fill a moldcavity half full. A contact lens was then placed, convex side down, ontop of the molten agar and additional agar was added on top tocompletely encase each lens in agar. Each plate contained 12 moldcavities and upon forming all 12, the plate was placed at 4° C. for 10minutes until it is completely solidified. Once solid, a small brasspunch of the same diameter as the contact lens (14 mm) was used to puncha hole in the agar around each lens. A hand held vacuum suction cup wasused to pull the top of the agar mold off, tweezers were used to removethe silicone hydrogel lens, and then the top of the mold was replaced.This is repeated for each mold. Molds were then ready to be used forhydrogel attachment.

Example 5

Preparation of poly(ethylene glycol) hydrogel macromer solutions. ThePEG hydrogel consists of two components. The first is 8-arm, 10 kDapoly(ethylene glycol) (PEG) end functionalized with vinyl sulfone(PEG-VS). The second is 4-arm, 10 kDa PEG end functionalized with thiolgroups (PEG-SH). The PEG-VS was dissolved to 10% w/v in triethanolaminebuffer (TEOA) at pH 8.0 and then filter sterilized in a 0.45 micron PVDFfilter. The PEG-SH was dissolved to 10% w/v in distilled water and thenfilter sterilized in a 0.45 micron PVDF filter.

Example 6

Fabrication of a PEG hydrogel. To form a PEG hydrogel, the macromersolutions of Example 5 were mixed together. To achieve varying polymerconcentrations, a diluting volume of TEOA was added to the PEG-VSsolution prior to mixing. The components were combined together with a10% molar excess of thiol groups. The table below lists quantities usedto fabricate various weight percentage PEG hydrogels. For example, toform a 5% PEG hydrogel: 96 μL of TEOA, was added to 30 μL of PEG-VS inan eppendorf tube. Finally, 66 mL of PEG-SH was added to the tube and itis mixed using a vortex for 3 seconds to ensure complete mixing. The PEGhydrogel was then incubated at 37° C. for 1 hour to ensure completepolymerization.

Volume (μL) Hydrogel TEOA PEG-VS PEG-SH Total 4% 115.2 24.0 52.8 192.05% 96.0 30.0 66.0 192.0 6% 76.8 36.0 79.2 192.0 7% 57.6 42.0 92.4 192.08% 38.4 48.0 105.6 192.0 9% 19.2 54.0 118.8 192.0 10% 0.0 60.0 132.0192.0

Example 7

Determining a non-swelling PEG hydrogel formulation. PEG hydrogelmacromer solutions of Example 6 were pipetted between two hydrophobicglass slides separated by a 1 mm spacer and allowed to incubate at 37°C. for 1 hour. To determine swelling ratio, the PEG hydrogel was weighedimmediately following polymerization and then immersed in distilledwater for 24 hours. The swollen PEG hydrogel was weighed again todetermine the amount of water absorbed into the polymer network todetermine the mass fold increase. The mass change for all PEG hydrogelformulations was small and the PEG hydrogel formulation of 5% did notundergo any swelling following polymerization.

Example 8

Fabricating a Contact Lens with a bulk layer of PEG Hydrogel on theConcave Side. To produce a contact lens with a bulk layer of PEGhydrogel, the molds of Example 3 were prepared using sacrificial lensesidentical to those receiving a bulk layer of PEG hydrogel. A solution of50% by volume TEOA, 34.4% PEG-SH, and 15.6% PEG-VS were prepared bymixing in an eppendorf tube and vortexing. The top of the agar mold wasremoved using a small hand held vacuum suction device and thefunctionalized lens (of either Example 1 or Example 2 or Example 3) wereplaced into the mold. 20 μL of the mixed PEG solution was placed ontothe concave side of the lens, and the top of the agar mold was replacedon top. Air bubbles were removed by gently tapping on the top of themold until all air was removed from the mold. The mold was placed in anincubator at 37° C. for 1 hour. The lenses were then removed, visuallyinspected, and placed in purified water for storage.

Example 9

Fabricating a Contact Lens with a bulk layer of PEG Hydrogel on theConvex Side. To produce a contact lens with a bulk layer of PEGhydrogel, the molds of Example 3 were prepared using sacrificial lensesidentical to those receiving a bulk layer of PEG hydrogel. A solution of50% by volume TEOA, 34.4% PEG-SH, and 15.6% PEG-VS were prepared bymixing in an eppendorf tube and vortexing. The top of the agar mold wereremoved using a small hand held vacuum suction device and 20 μL of themixed PEG solution was placed into the bottom of the mold. Thefunctionalized lenses (of either Example 1 or Example 2 or Example 3)were placed into the mold and the top of the agar mold was replaced ontop. Air bubbles were removed by gently tapping on the top of the molduntil all air was removed from the mold. The mold was placed in anincubator at 37° C. for 1 hour. The lenses are then removed, visuallyinspected, and placed in purified water for storage.

Example 10

Fabricating a Contact Lens with a bulk layer of Hydrogel on both Concaveand Convex Sides (Encased). To produce a contact lens encased in a bulklayer of PEG hydrogel, the molds of Example 4 were prepared usingsacrificial lenses identical to those receiving a bulk layer of PEGhydrogel. A solution of 50% by volume TEOA, 34.4% PEG-SH, and 15.6%PEG-VS was prepared by mixing in an eppendorf tube and vortexing. Thetop of the agar mold was removed using a small hand held vacuum suctiondevice and 20 μL of the mixed PEG solution is placed into the bottom ofthe mold. The functionalized lens (of either Example 1 or Example 2 orExample 3) were placed into the mold and 20 μL of the mixed PEG solutionwas placed onto the concave side of the lens and then the top of theagar mold was placed on top. Air bubbles were removed by gently tappingon the top of the mold until all air was removed from the mold. The moldwas placed in an incubator at 37° C. for 1 hour. The lenses were thenremoved, visually inspected, and placed in purified water for storage.

Example 11

Oaysys Lenses Encapsulated in PEG Hydrogel. Contact lenses (AcuvueOaysys, lotrafilcon A) were functionalized according to Example 1. Agarmolds were prepared according to Example 4. Lenses were encapsulatedaccording to Example 10.

Example 12

Oaysys Lenses with a bulk layer of PEG Hydrogel. Contact lenses (AcuvueOaysys, lotrifilcon A) were functionalized according to Example 1. Agarmolds were prepared according to Example 4. A bulk layer was addedaccording to Example 8.

Example 13

PureVision Lenses Encapsulated in PEG Hydrogel. Contact lenses(PureVision, balafilcon A) were functionalized according to Example 1.Agar molds were prepared according to Example 4. Lenses wereencapsulated according to Example 10.

Example 14

PureVision Lenses with a bulk layer of PEG Hydrogel. Contact lenses(PureVision, balafilcon A) were functionalized according to Example 1.Agar molds were prepared according to Example 4. A bulk layer was addedaccording to Example 8.

Example 15

Silicone Lenses Encapsulated in a bulk layer of PEG Hydrogel. Siliconelenses (NuSil, Med 6755) were functionalized according to Example 2.Agar molds were prepared according to Example 4. Lenses wereencapsulated according to Example 10.

Example 16

Silicone Lenses with a bulk layer of PEG Hydrogel on the Concave Side.Silicone lenses (NuSil, Med 6755) were functionalized according toExample 2. Agar molds were prepared according to Example 4. A bulk layerwas added according to Example 8.

Example 17

Silicone Lenses with a bulk layer of PEG Hydrogel on the Convex Side.Silicone lenses (NuSil, Med 6755) were functionalized according toExample 2. Agar molds were prepared according to Example 4. A bulk layerwas added according to Example 9.

Example 18

Contact Angle Measurement. To measure lens contact angles, the captivebubble technique was used. First, the lens was spun in a vortex indistilled water to remove surface contaminants. The lens was thensubmerged in distilled water and suspended atop a plate that has a holethrough which the convex surface of the lens protrudes downward. An11/16″ diameter stainless steel ball was placed atop the lens to keep itin place when the bubble was applied. Next, the curved tip of a 16 gaugeblunt needle was placed just below the surface of the center of thelens. A bubble was then advanced until it makes contact with the lens,at which point the bubble was retracted until it breaks free from eitherthe lens or the needle. A high-definition video camera records theentire procedure, after which an image was saved from the frameimmediately preceding the moment the bubble detaches from either thelens or the needle. From this image, the angles between the lens and thebubble on both sides of the bubble were calculated in MATLAB and savedas the contact angles for that lens.

Example 19

Contact Angle Measurement of Oasys Lenses with bulk layers of PEGHydrogel. The contact angle of lenses of Example 11 were measuredaccording to Example 18.

Lens with bulk layers of PEG hydrogel Contact Angle* Lens 1 12.3 Lens 214.6 Lens 3 10.7 Average 12.5 *Contact angle is the average of 3 tests

Example 20

Preparation of photo-polymerizable poly(ethylene glycol) hydrogelmacromer solutions. The hydrogel consists of two components. The firstis 8-arm, 10 kDa poly(ethylene glycol) (PEG) end functionalized withacrylate (PEG-Ac). The second is 4-arm, 10 kDa PEG end functionalizedwith thiol groups (PEG-SH). The PEG-Ac is dissolved to 10% w/v intriethanolamine buffer (TEOA) at pH 8.0 and then filter sterilized in a0.45 micron PVDF filter. The PEG-SH is dissolved to 10% w/v in distilledwater and then filter sterilized in a 0.45 micron PVDF filter.

Example 21

Fabrication of a photo-polymerizable PEG hydrogel. To form a hydrogel,the macromer solutions of Example 20 are mixed together. To achievevarying polymer concentrations, a diluting volume of TEOA is added tothe PEG-Ac solution prior to mixing. The components are combinedtogether with a 10% molar excess of thiol groups. The table below listsquantities used to fabricate various weight percentage hydrogels. Forexample, to form a 5% PEG hydrogel: 96 μL of TEOA, is added to 30 μL ofPEG-Ac in an eppendorf tube. Finally, 66 mL of PEG-SH is added to thetube and it is mixed using a vortex for 3 seconds to ensure completemixing. The solution is then exposed to UV light (365 nm, 5 mW/cm2, 10min) to polymerize the mixture.

Volume (μL) Hydrogel TEOA PEG-Ac PEG-SH Total 4% 115.2 24.0 52.8 192.05% 96.0 30.0 66.0 192.0 6% 76.8 36.0 79.2 192.0 7% 57.6 42.0 92.4 192.08% 38.4 48.0 105.6 192.0 9% 19.2 54.0 118.8 192.0 10% 0.0 60.0 132.0192.0

Example 22

Layer by Layer Reactive Spin Coating. The macromer solutions of Example20 are prepared. Lenses of Example 1 or 2 or Example 3 are fixed to aspin coater chuck. The lenses are rotated at speeds ranging from500-5000 rpms. While revolving, the lens is continuously exposed to UVlight (365 nm, 5 mW/cm2), while drops of macromer solution arealternately added to the lenses as follows: 10 μL of PEG-Ac followed by10 μL of PEG-SH, etc. This is repeated for multiple cycles, ranging from10-1000.

Example 23

PEG Dipping Solution for Enzyme Mediated Redox Chain Initiation. The PEGdipping solution consists of a mixture of glucose oxidase (GOX), Fe+2,and polyethylene glycol diacrylate (PEGDA) (MW from 2,000 Da-10,000 Da).For example, a dipping solution may contain 3.1×10-6 M GOX, 2.5×10-4 Miron (II) sulfate, 10% PEGDA 5,000 Da.

Example 24

Contact Lens Encapsulated in PEG Hydrogel Via Interfacial EnzymeMediated Redox Chain Initiation. The glucose loaded lenses of Example 18are dipped into the solution of Example 19 until the hydrogel layergrows to the desired thickness. The time to achieve a layer thickness of10-100 microns ranges from 2 seconds-10 minutes.

Example 25

Captive Bubble Contact Angle Measurement. A macro lens of 10×magnification was affixed to the camera detailed in Example 17, ContactAngle Measurement. The macro lens enables close-up movies of thebubble/contact lens interface. A syringe pump (New Era Syringe Pump 750)was added to the testing fixture to enable continuous and repeatablebubble control. The pump was programmed using Syringe Pump Proprogramming software. A new test fixture chamber was constructed ofblack acrylonitrile butadiene styrene (abs) to facilitate the use of athin, clear, glass viewing plate and a semi-opaque background screen.The tested lens were held between two plates and submerged in PBS. Anair bubble was extended 2 mm from a straight 16 gage blunt needle untilit made contact with the lens. A high-definition web camera recorded thelens+bubble interface while 3 μl of air was infused and then withdrawnat a rate of 7.2 μl/min from the micro-syringe (Precision Sampling corp,series A-2, 25 ul).

Example 26

PEG Concentration Dependence. To determine the effect of PEGconcentration on polymerization rate for the hydrogel, the macromersolutions of Example 4 were combined at decreasing concentrations andchecked at set time intervals until solidification. PEG-VS and PEG-SHwere combined in the below quantities with the specified quantity of0.2M TEOA in 1.5 ml eppendorf tubes to form the noted concentrations.Each solution was vortexed and then pippted onto a glass slide. The PEGsolution was pippeted at 5, 10, or 30 second intervals (increasing timeinterval for lower concentrations) until filaments formed, indicatingthat the gel had polymerized. The time-until-polymerization wasrecorded.

PEG Concentration 1% 2% 3% 4% 6% 8% 10% Volume PEG-VS 10.6 10.6 16.021.3 31.9 42.6 53.2 (μL) PEG-SH 19.4 19.4 29.0 38.7 58.1 77.4 96.8 TEOA270 120 105 90 60 30 0 Total Volume 300 150 150 150 150 150 150Polymerization 8820 680 406 250 150 103 83 Time (Sec)

Example 27

PEG pH Dependence. To determine the polymerization rate of the hydrogelas a function of pH, the macromer solutions of Example 4 were combinedwith 0.2M TEOA at increasing pH levels. 20% PEG-VS and 10% PEG-SH werecombined in the below quantities with TEOA at the specified pH in 1.5 mleppendorf tubes. The TEOA buffer was prepared at the notedconcentrations by adjusting pH with NaOH or HCl as required. A 4%hydrogel solution was made. Each solution was vortexed and then pipptedonto a glass slide. The PEG solution was pippeted at 5, 10, or 30 secondintervals (increasing time interval for lower pH) until filamentsformed, indicating that the gel had polymerized. Thetime-until-polymerization was recorded.

Example 28

Lenses Dip Coated to Obtain a Bulk Layer of PEG. Lenses werefunctionalized using nitrogen gas in a plasma chamber (Plasma EtchPE-50) at settings: 375 mTorr, 3 min, 100% RF power. Pressure wasreduced to 375 milliTorr with continuous flow of nitrogen gas at 10-20standard cubic centimeters per minute. The chamber was allowed tostabilize for 30 seconds before initiating plasma at 100 W for 3minutes. The chamber was then vented to atmosphere and lenses removed.Lenses were then used within 1 hour. The PEG macromer solutions ofExample 4 were combined with excess TEOA to obtain solutions with atotal solids concentration of 0.1% and 0.5% and with a 10% molar excessof VS (See quantities in table below). A 0% PEG solution was alsoprepared as a control. The volume of 0.2M TEOA detailed below was addedto individual plastic vials (McMaster Carr 4242T83); followed by thenoted volume of PEG-VS. The surface functionalized PureVision lenseswere added to this solution and vortexed. The PEG-SH was added and thesolution was again vortexed. The lenses were placed on a mixing tablefor 24 hrs. The lenses were transferred to new plastic vials containingPhosphate Buffered Saline (PBS) and placed on the mixing table for 24hrs. The lenses were transferred to glass jars and autoclaved (Tuttnauer3870 E) in a wet cycle at 250° F. for 30 min.

PEG Concentration 0.00% 0.1% 0.5% Volume (μL) PEG-VS 0.0 5.3 26.6 PEG-SH0.0 9.7 48.4 TEOA 1500 1485 1425 Total 1500 1500 1500

Example 29

Silicone Lenses Surface Activated to Enhance Hydrogel Adhesion. Siliconelenses (NuSil, Med 6755) were functionalized with the plasma treatmentprocess of Example 28. In a 50 mL conical tube, the lenses were placedin a 10% w/v divinyl sulfone solution with a sodium bicarbonate bufferat pH 11 and vortexed. After 1 hr on a mixing table, the lenses werewashed with 20 ml of deionized water (DI Water) and placed back on themixing table in 40 ml of DI water. After 1 hr, this cycle was repeatedonce more and the lenses were placed in the fridge for 8 hrs in 40 ml ofDI water.

Example 30

Silicone Lenses Dip Coated to Obtain a Bulk Layer of PEG. Siliconelenses (NuSil, Med 6755) were functionalized, dip coated and autoclaved,in the 0%, 0.1%, and 0.5% PEG solutions per Example 28.

Example 31

PureVision Lenses Surface Activated and Dip Coated to Obtain a Bulk PEGLayer. Contact lenses (PureVision, balafilcon A) were functionalizedwith the plasma treatment process of Example 28. The lenses were placedinto 400 uL of 10% PEGVS, vortexed, and then positioned on the mixingtable for 5 minutes. Subsequently, the lenses were placed in 3 mL of0.2M TEOA, vortexed, and set on the mixing table for 5 minutes. Thelenses were added to a solution of 0.1% PEG in TEOA according to example28. The lenses were vortexed, stationed on the mixing table for 24 hrs,and autoclaved according to Example 28.

Example 32

PureVision Lenses Dip Coated with FITC-Maleimide Addition for PEG LayerVisualization. Contact lenses (PureVision, balafilcon A) werefunctionalized with the plasma treatment process of Example 28. Thelenses were placed into 0.1% and 0.5% PEG solutions according to example28. 5.1 μl of FITC-Maleimide @ 10 mg/mL was added to each of thesolutions to visualize the PEG layer. The solutions were vortexed andplaced on a mixing table for 24 hrs.

Example 33

PureVision Lenses Dip Coated to Obtain a Bulk Layer of PEG withShortened Wash Cycle. Contact lenses (PureVision, balafilcon A) werefunctionalized and coated according to Example 28. After 24 hrs in thePEG solution, the lenses were placed in vials containing PBS and placedon the mixing table for 1.5 hrs. The lenses were placed in a second setof vials containing PBS and placed on the mixing table for 1.5 hrs. Thelenses were autoclaved according to Example 28.

Example 34

PureVision Lenses Dip Coated in Ultra-Low Concentration PEG with No WashCycle. Contact lenses (PureVision, balafilcon A) were functionalizedwith the plasma treatment process of Example 28. The macromer solutionsof Example 4 were combined with TEOA at 0.01% and 0.05% PEG. A 0% PEGsolution was also prepared as a control. The PureVision lenses wereadded to this solution and vortexed. The PEG-SH was added and thesolution was again vortexed. The lenses were autoclaved in individualplastic vials for 30 min at 250° F. without being washed and withoutbeing removed from the PEG solution.

PEG Concentration 0.00% 0.01% 0.05% Volume PEG-VS 0.0 0.53 2.66 (μL)PEG-SH 0.0 .97 4.84 TEOA 1500 1498.5 1492.5 Total 1500 1500 1500

Example 35

PureVision Lenses Dip Coated in Low Concentration PEG with ImmediateAutoclave in Glass. Contact lenses (PureVision, balafilcon A) werefunctionalized and coated according to Example 28. The lenses wereplaced in glass vials (McMaster-Carr 4417T48) containing 3 ml of PBS andautoclaved according to Example 28.

Example 36

PureVision Lenses Dip Coated and Extracted in Isopropanol Alcohol.Contact lenses (PureVision, balafilcon A) were functionalized and coatedat the 0% and 0.5% concentrations according to Example 28. The lenseswere placed on a mixing table for 18 hrs. The PEG solution was replacedwith pure isopropanol alcohol (IPA) and returned to the mixing table for1 hr. The IPA was switched and the lenses were washed for an additionalhour. The IPA was replaced with deionized water and the lenses werewashed for 1 hr. The water was replaced twice and the lenses were washedfor 30 min each time. The lenses were placed in PBS and autoclaved perExample 28.

Example 37

PureVision Lenses Dip Coated in Organic Solvents to Obtain Bulk Layer ofPEG. 1 ml of pure TEOA was added to 40 ml of isopropyl alcohol (IPA) tomake a 0.2M solution. Pure Methanol was added to IPA at 0.2M TEOA tocreate a 50% solution. 1 ml of concentrated TEOA was dissolved into 40ml of pure Methanol (MeOH) to form a MeOH at 0.2 Molar TEOA solution.Contact lenses (PureVision, balafilcon A) were functionalized with theplasma treatment process of Example 28. The macromer solutions ofExample 4 were combined with the 50% MeOH and 50% IPA at 0.2M TEOA at0.5% PEG. A 0% PEG solution was also prepared as a control. The macromersolutions of Example 4 were also combined with the MeOH at 0.2 M TEOA at0.5% PEG. The volume of MeOH and IPA detailed below were added toindividual plastic vials; the surface functionalized PureVision lenseswere added to the solution and vortexed. The PEG-VS and PEG-SH wereadded and the solution but the solution was not vortexed due to thesensitivity of the lenses in solvents. The lenses were placed on amixing table for 18 hrs. A washing series was utilized to remove theorganic solvents; the solutions were changed to pure IPA and the lenswere placed on the mixing table for 1 hr. The IPA was replaced withdeionized (DI) water and the lenses were placed on the mixing table for1 hr. The DI water was replaced with PBS and the lenses were autoclavedper Example 28.

Example 38

PureVision Lenses with DVS Activation during IPA Solvent Extraction. 1ml of 100% TEOA was added to 40 ml of isopropyl alcohol (IPA) to make a0.2M solution. Contact lenses (PureVision, balafilcon A) werefunctionalized according to Example 28 and placed in 5 ml of IPA at 0.2MTEOA. Non-plasma treated and no-peg lenses were also prepared ascontrols. 7.5% DVS was added to each vial. The lenses were swirled inthe solution and then placed on the mixing table for 1 hour. The DVS wasdiscarded and 40 ml of IPA was added to each solution prior to placingthe lenses on the mixing table for 1 hour. The IPA was changed and thelenses were placed on the mixing table for 1 hr. The IPA was replacedwith 40 ml of deionized (DI) water and mixed for 1 hr. The DI water waschanged and the lenses were mixed for 1 hr. The lenses were dip coatedand autoclaved according to Example 28.

Example 39

PureVision Lenses with DVS Activation during MeOH Solvent Extraction. 1ml of 100% TEOA was added to 40 ml of methanol alcohol (MeOH) to make a0.2M solution. Contact lenses (PureVision, balafilcon A) werefunctionalized according to Example 28 and placed in 5 ml of MeOH at0.2M TEOA. Non-plasma treated and no-peg lenses were also prepared ascontrols. 7.5% DVS was added to each vial. The lenses were swirled inthe solution and then placed on the mixing table for 1 hour. The DVS wasdiscarded and 40 ml of IPA was added to each solution prior to placingthe lenses on the mixing table for 1 hour. The IPA was changed and thelenses were placed on the mixing table for 1 hr. The IPA was replacedwith 40 ml of deionized (DI) water and mixed for 1 hr. The DI water waschanged and the lenses were mixed for 1 hr. The lenses were dip coatedand autoclaved according to Example 28.

Example 40

PureVision Lenses Dip Coated in Methanol Solvent to Obtain a Bulk Layerof PEG. Contact lenses (PureVision, balafilcon A) were functionalizedaccording to Example 28. A MeOH at 0.2 Molar TEOA solution was madeaccording to Example 39. The macromer solutions of Example 4 werecombined with the MeOH at 0.2 M TEOA at 0.1%, 0.25% and 0.5% PEG. A 0%PEG solution was also prepared as a control. The volume of MeOH detailedbelow was added to individual glass vials; followed by the noted volumeof PEG-VS. The surface functionalized PureVision lenses were added tothis solution and vortexed. The PEG-SH was added and the solution wasagain vortexed. The lenses were placed on a mixing table for 24 hrs.

A MeOH washing cycle was developed and implemented: The MeOH at 0.2 MTEOA and PEG solution was replaced with pure MeOH and the lenses wereplaced on the mixing table for 1 hr. The MeOH was replaced with IPA andthe lenses were placed on the mixing table for 1 hr. The IPA wasreplaced with a solution consisting of 50% IPA and 50% DI water and thelenses were placed on the mixing table for 1 hr. The 50% solution wasreplaced with 100% DI water and the lenses were placed on the mixingtable for 1 hr. The DI water was replaced with Phosphate Buffered Saline(PBS) and autoclaved according to Example 28.

PEG Concentration 0.00% 0.1% 0.25% 0.5% Volume PEG-VS 0.0 5.3 13.25 26.6(μL) PEG-SH 0.0 9.7 24.25 48.4

 at 0.2M TEOA 1500 1485 1462.5 1425 Total 1500 1500 1500 1500

Example 41

Plasma Treatment Process. The setting for the plasma treatment processwere tested and updated. The plasma treatment process used nitrogen gas,grade 5, in a plasma chamber (Plasma Etch PE-50) with settings: 150mTorr set point, 200 mtorr vacuum, 3 min, @ 100% RF power. Pressure wasreduced to 200 milliTorr with continuous flow of nitrogen gas at 2.5-5standard cubic centimeters per minute. The chamber was allowed tostabilize for 30 seconds before initiating plasma at 100 W for 3minutes. The chamber was then vented to atmosphere and lenses removed.Lenses were then used within 1 hour.

Example 42

Lenses Extracted in Isopropanol Alcohol, Desiccated, and Dip Coated.Lenses were placed in 1.5 ml of IPA and set on a mixing table for 18hrs. The IPA was switched and the lenses were washed for an additionalhour. The IPA was replaced with deionized water and the lenses werewashed for 1 hr. The water was replaced twice and the lenses were washedfor 30 min each time. The lenses were placed in a vacuum chamber and thechamber was evacuated using a pump (Mastercool, 6 cfm) for 24 hrs. Thelenses were functionalized and coated at the 0% and 0.5% concentrationsaccording to Example 28 with the plasma treatment process of Example 41.The PEG solution was replaced with deionized water and the lenses werewashed for 1 hr. The lenses were placed in PBS and autoclaved perExample 28.

Example 43

PureVision Lenses Dip Coated to Obtain a Bulk Layer of PEG. Example 28was repeated using the plasma treatment process of Example 41.

Example 44

PureVision Lenses Dip Coated in Low Concentration PEG with ImmediateAutoclave in Glass. Example 36 was repeated using the plasma treatmentprocess of Example 41.

Example 45

PureVision Lenses Dip Coated in Organic Solvents to Obtain Bulk Layer ofPEG. Example 38 was repeated using the plasma treatment process ofExample 41.

Example 46

PureVision Lenses Dip Coated in Methanol Solvent to Obtain a Bulk Layerof PEG. Example 40 was repeated using the plasma treatment process ofExample 41.

Example 47

PureVision Lenses Extracted in Isopropanol Alcohol, Desiccated, DipCoated, with Immediate Autoclave. Contact lenses (PureVision, balafilconA) were extracted, desiccated, and dip coated according to Example 42.Immediately after the dip coating process the lenses were autoclavedwhile in the PEG solution according to Example 28.

Example 48

Silicone Lenses Extracted in Isopropanol Alcohol, Desiccated, and DipCoated. Silicone contact lenses (NuSil, Med 6755) were extracted,desiccated, dip coated and autoclaved according to Example 42.

Example 49

PureVision Lenses Extracted in Isopropanol Alcohol, Desiccated, and DipCoated. Contact lenses (PureVision, balafilcon A) lenses were extracted,desiccated, dip coated and autoclaved according to Example 42.

Example 50

PureVision Lenses Dip Coated in Methanol Solvent with Heated Rotation toObtain a Bulk Layer of PEG. Contact lenses (PureVision, balafilcon A)were functionalized using oxygen gas in a plasma chamber (Plasma EtchPE-50) at settings: 200 mTorr, 3 min, 100% RF power. The lenses were dipcoated according to Example 40 and placed in a heated oven with rotationat 37° C. for 24 hours. The lenses were washed and autoclaved accordingto Example 40, but with the following shortened wash times: MeOH 2×quick swirls, IPA 2×20 min, IPA:H20 (50:50) 20 min, H20 10 min, and PBSfor autoclave.

Example 51

Silicone Lenses Dip Coated in Methanol Solvent with Heated Rotation toObtain a Bulk Layer of PEG. Silicone contact lenses (NuSil, Med 6755)were functionalized using oxygen gas in a plasma chamber (Plasma EtchPE-50) at settings: 200 mTorr, 3 min, 100% RF power. The lenses were dipcoated according to Example 40 and placed in a heated oven with rotationat 37° C. for 24 hours. The lenses were washed and autoclaved accordingto Example 40, but with the following shortened wash times: MeOH 2×quirk swirls, IPA 2×20 min, IPA:H20 (50:50) 20 min, H20 10 min, and PBSfor autoclave.

Example 52

PureVision Lenses Pre-Activated, Dip Coated in Methanol Solvent withHeated Rotation. Lenses (PureVision, balafilcon A) were functionalizedusing oxygen gas in a plasma chamber (Plasma Etch PE-50) at settings:200 mTorr, 3 min, 100% RF power. The lenses were pre-activated withPEG-VS or VS, dip coated according to Example 40 and placed in a heatedoven with rotation at 37 C for 24 hours. The lenses were washed andautoclaved according to Example 40, but with the following shortenedwash times: MeOH 2× quick swirls, IPA 2×20 min, IPA:H20 (50:50) 20 min,H20 10 min, and PBS for autoclave.

Example 53

Silicone Lenses Dip Coated to Obtain a Bulk Layer of PEG. Example 30 wasrepeated using the plasma treatment process of Example 41.

Example 54

PureVision Lenses Dip Coated to Obtain a Bulk Layer of PEG using OxygenGas. Example 28 was repeated using oxygen gas, grade 5, during theplasma treatment process.

Example 55

PureVision Lenses Plasma Treated and Dip Coated in Hyaluronic Acid toObtain a Bulk Layer. Contact lenses (PureVision, balafilcon A) werefunctionalized according to Example 28 with the addition hyaluronic acid(HA) at of 10 mg of hyaluronic acid (HA). Lenses were added to thissolution and placed on the mixing table for 1 hr. The HA solution wasreplaced with DI water and the lenses were placed on a mixing table for1 hr. The water was replaced and the lenses were placed on a mixingtable for 1 hr, 2 additional times. The lenses were placed in individualplastic vials containing 3 ml-5 ml of PBS.

Example 56

PureVision Lenses Plasma Treated and Surface Activated with DVS in NaOH.Contact lenses (PureVision, balafilcon A) were functionalized accordingto Example 28. 0.5 ml of DVS was added to 4.5 ml of 0.5M SodiumBiCarbonate (NaOH). Lenses were added to this solution and placed on themixing table for 20 min. Lenses were also placed in 5 ml of NaOH ascontrols. The solution was replaced with DI water and the lenses wereplaced on the mixing table for 20 min. This step was repeated 2additional times.

Example 57

PureVision Lenses Plasma Treated and Dip Coated in Hyaluronic Acid toObtain a Bulk Layer with a FITC-Maleimide Addition for LayerVisualization. Contact lenses (PureVision, balafilcon A) werefunctionalized according to Example 28 and dip coated according toExample 55. 51 μl of FITC-Maleimide was added to each of the solutionsto visualize the PEG layer. The lenses were washed and stored accordingto Example 55.

Example 58

PureVision Lenses Plasma Treated and Dip Coated in Hyaluronic Acid inNaOH to Obtain a Bulk Layer. Contact lenses (PureVision, balafilcon A)were functionalized according to Example 28. 5 ml of HA was added to 45ml of 10M NaOH. 5 ml of HA was added to 45 ml of DI water for a control.Lenses were added to these solutions and placed on the mixing table for1 hr. The solutions were replaced with DI water and the lenses wereplaced on the mixing table for 1 hr. The lenses were placed inindividual plastic vials containing 3 ml-5 ml of PBS.

Example 59

Silicone Lenses Plasma Treated then Encapsulated in PEG Hydrogel.Silicone lenses (NuSil, Med 6755) were functionalized according toExample 28. Agar molds were prepared according to Example 4. Lenses wereencapsulated according to Example 10.

Example 60

PureVision Lenses Plasma Treated and Dip Coated in Low or High MolecularWeight PEG. Contact lenses (PureVision, balafilcon A) werefunctionalized using monofunctional polyethylene glycol, endfunctionalized in vinyl sulfone (mPEG-VS). mPEGs of 5 kDa and 20 kDawere used.

5% w/v total mPEG-VS solutions were prepared in triethanolamine buffer(TEOA) at pH 8.0 and then filter sterilized in a 0.45 micron PVDFfilter. A 0% PEG solution was also prepared as a control.

3 ml of PEG solution was added to individual plastic vials (McMasterCarr 4242T83). The surface functionalized PureVision lenses were addedto this solution and vortexed. The lenses were placed on a mixing tablefor 24 hrs. The lenses were transferred to new plastic vials containingPhosphate Buffered Saline (PBS) and placed on the mixing table for 24hrs.

Example 61

Silicone Lenses Plasma Treated then Encapsulated in PEG Hydrogel with aFITC-Maleimide Addition for PEG Layer Visualization. Silicone lenses(NuSil, Med 6755) were functionalized according to Example 28. Agarmolds were prepared according to Example 4. 5.1 μl of FITC-Maleimide wasadded to each of the solutions to visualize the PEG layer. Lenses wereencapsulated according to Example 10.

Example 62

Oaysys Lenses Desiccated and Plasma Treated then Encapsulated in PEGHydrogel. Contact lenses (Acuvue Oaysys, senofilcon A) were desiccatedaccording to Example 42 and functionalized according to Example 28. Agarmolds were prepared according to Example 4. Lenses were encapsulatedaccording to Example 10.

Example 62

Lenses Encapsulated in PEG Hydrogel. Lenses (Lotrafilcon B) werefunctionalized according to Example 1. Agar molds were preparedaccording to Example 4. Lenses were encapsulated according to Example10.

Example 63

Lenses Desiccated and Plasma Treated then Encapsulated in PEG Hydrogel.Lenses (Lotrafilcon B) were desiccated according to Example 42 andfunctionalized according to Example 28. Agar molds were preparedaccording to Example 4. Lenses were encapsulated according to Example10.

Example 64

Silicone Lenses Plasma Treated and Dip Coated in Low or High MolecularWeight PEG. Silicone lenses (NuSil, Med 6755) were functionalizedaccording to Example 28, with the addition of a non-plasma treatedcontrol, and dip coated according to Example 60.

Example 65

PureVision Lenses Plasma Treated then Encapsulated in PEG Hydrogel.Contact lenses (PureVision, balafilcon A) were functionalized accordingto Example 28. Agar molds were prepared according to Example 4. Lenseswere encapsulated according to Example 10.

Example 66

PureVision Lenses Dip Coated to Obtain a Bulk Layer of PEG. Contactlenses (PureVision, balafilcon A) were functionalized and coatedaccording to Example 28. The lenses were washed according to example 33and autoclaved according to Example 28.

Example 67

Glucose Loading of Hydrogel Contact Lenses. Hydrogel contact lensescontaining acrylate groups on the surface were incubated in d-Glucosesolution (10 mL/lens) for at least 4 hours. The glucose concentrationmay range from 0.1 mM to 25 mM.

Example 68

PureVision Lenses Dip Coated and Accelerated Life Tested to Identify theStability of the Bulk Layer of PEG. Example 46 was repeated; contactlenses (PureVision, balafilcon A) dip coated in methanol solvent toobtain a bulk layer of peg. Post autoclave process according to Example28, the lenses were tested according to Example 25. The lenses wereplaced in PBS and autoclaved once more according to Example 28 or placedin sterile saline (Walgreens—Sterile Saline Solution). The lenses wereplaced in hybridization ovens (Stovall Life Science Inc) at 20, 40, or60 degrees Centigrade. The lenses were tested on dates that correspondto six or twelve months of accelerated life testing as detailed by FDA510K clearance requirements for medical devices generally, and dailywear contacts specifically. Post testing, the sterile saline wasreplaced with new sterile saline and the lenses were replaced in therespective hybridization oven. Lot numbers with corresponding solutionsand temperatures are detailed below.

0% PEG Storage n = 6 Solution Temp [C.] Saline Sterile Saline 20 M167M170 45 M168 M171 60 M169 M172

0.5% PEG n = 6 Storage Solution Temp [C.] Saline Sterile Saline 20 M173M176 45 M174 M177 60 M175 M178

Example 69

MJS Lenses Dip Coated to obtain a Bulk Layer of PEG. MJS Lenses (MJSLens Technology Ltd, Standard Product, 55% water content) werefunctionalized according to Example 41, coated and autoclaved accordingto Example 28, and tested according to Example 25. The lenses were thenplaced in hybridization ovens (Stovall Life Science Inc) at 60 degreesCelsius for 7 days. The sterile saline (Walgreens—Sterile SalineSolution) was replaced and the lenses were retested according to Example25.

Example 70

Determining water content of poly(ethylene glycol) coated contact lensesutilizing mass balance. This example illustrates how to determine thewater content of a contact lens of the invention. In an effort todetermine the potential water content of the polyethylene-glycollayer(s) of the contact lenses of the invention, samples consisting ofthe layer components are prepared for evaluation. The resulting gels arethen hydrated and tested to determine water content.

PEG hydrogel macromer solutions as described in Example 5 were pipettedbetween two hydrophobic glass slides separated by a 1 mm spacer andallowed to incubate at 37° C. for 1 hour.

Hydrated samples were blotted dry and the mass at hydrated state wasrecorded via mass balance. Following the recording of the mass athydrated state, the samples were all dried under a vacuum of <1 inch Hgovernight.

Dried samples were removed from the vacuum oven after overnight dryingand then measured to record dry mass. Water content was calculated usingthe following relationship: Water content=[(wet mass-dry mass)/wetmass]×100%

Example 71

Preparation of Poly(ethylene glycol) Hydrogel Macromer Solutions. In oneexample, the PEG hydrogel consists of two components. The first is8-arm, 10 kDa poly(ethylene glycol) (PEG) end functionalized with vinylsulfone (PEG-VS). The second is 4-arm, 10 kDa PEG end functionalizedwith thiol groups (PEG-SH). The PEG-VS was dissolved to 10% w/v intriethanolamine buffer (TEOA) at pH 8.0 and then filter sterilized in a0.45 micron PVDF filter. The PEG-SH was dissolved to 10% w/v indistilled water and then filter sterilized in a 0.45 micron PVDF filter.

Example 72

Contact Lenses. In another example, the following lenses and materialswere each processed through the subsequent examples: Silicone (NuSil,Med 6755); PureVision, balafilcon A; Acuvue Oaysys, senofilcon A; AIROPTIX, Lotrafilcon B, MJS Lenses, MJS Lens Technology Ltd. Allsubsequent references to ‘lenses’, include each of the above lenses andmaterials.

Example 73

Contact Lenses Dip Coated to Obtain a Bulk Layer of Poly(ethyleneglycol) (PEG) Hydrogel. In another example, commercially available andhydrated lenses were washed in deionized water three times for 30 mineach time. The lenses were desiccated in a vacuum chamber for 2-24 hrs.

Lens surfaces were functionalized using nitrogen gas in a standardplasma chamber (Plasma etch PE-50) at settings: 200 mTorr, 3 min, 100 WRF power, 5-20 standard cubic centimeters per minute. Lenses were thenused within 1 hour.

The PEG macromers were combined with either deionized water (DI Water),Isopropanol Alcohol (IPA), or Methanol (MeOH) @ 0.2M TEOA to obtainsolutions with a total solids concentration of 0.1%, 0.25% and 0.5%.Various concentrations of substrates were used; each solution was at a10% molar excess of VS (See quantities in table below) and a 0% PEGsolution was also prepared as a control.

The volume of substrate detailed below was added to individual vials,followed by the noted volume of PEG-VS. The surface functionalizedlenses were added to this solution. The PEG-SH was added and the lenseswere placed on a mixing table for 1 hr-24 hrs. The lenses were washedindividually in the corresponding substrate for 30 min. For the solventconditions, consecutive 30 min washes were in 100% IPA, 50% IPA in DIWater, and 100% DI Water. Lenses in the aqueous substrate were onlywashed in 100% DI water.

The lenses were placed in Phosphate Buffered Saline (PBS) and autoclavedin a wet cycle at 250° F. for 30 min. Lens general comfort and contactangle were determined through wear and direct in-house measurement,respectively.

PEG Concentration 0.00% 0.1% 0.25% 0.5% Volume PEG-VS 0.0 5.3 13.25 26.6(μL) PEG-SH 0.0 9.7 24.25 48.4 DI H20, IPA, or 1500 1485 1462.5 1425MeOH @ 0.2M TEOA Total 1500 1500 1500 1500

Example 74

Lenses Dip Coated with Recycled PEG. In another example, the steps ofabove Example 73 were repeated for contact lenses PureVision, balafilconA, at a 0.4M concentration of TEOA. The PEG from this process was kept.After 24 hrs, a PEG solution was developed using 50% of the original(750 μL) and 50% fresh or non-previously-used PEG. Example 73 wasrepeated using this PEG solution.

Example 75

Lenses Surface Activated using Hydrogen Peroxide and Dip Coated. Inanother example, dehydrated contact lenses PureVision, balafilcon A,were placed in commercially available Hydrogen Peroxide for 1 hr. Thelenses were washed with DI water for 30 min. The coating, washing,autoclave, and testing process was repeated according to Example 73.

Example 76

Lenses Extracted, Desiccated, and Dip Coated. In another example, lenseswere placed in 1.5 ml of IPA or MeOH (solvent) and set on a mixing tablefor 12-18 hrs. The solvent was switched and the lenses were washed inthe corresponding solvent for an additional hour. The solvent wasreplaced with deionized water and the lenses were washed three times for30 min to 1 hr each time. The lenses were desiccated in a vacuum chamberfor 2-24 hrs.

Lens surfaces were functionalized using nitrogen gas in a standardplasma chamber (Plasma etch PE-50) at settings: 200 mTorr, 3 min, 100 WRF power, 5-20 standard cubic centimeters per minute. Lenses were thenused within 1 hour. The lenses were coated, washed, autoclaved, andtested according to the aqueous process of Example 73.

Example 77

Lenses Dip Coated and Accelerated Life Tested to Identify the Stabilityof the Bulk Layer of PEG. In another example, the steps of Example 73were repeated; for contact lenses (PureVision, balafilcon A and MJS LensTechnology Ltd). Post autoclave and testing process, the lenses wereplaced in PBS and autoclaved once more or placed in sterile saline. Thelenses were placed in hybridization ovens (Stovall Life Science Inc) at20, 40, or 60 degrees Centigrade. The lenses were tested on dates thatcorrespond to six or twelve months of accelerated life testing asdetailed by FDA 510K clearance requirements for medical devicesgenerally, and daily wear contacts specifically. Post-testing, thesterile saline was replaced with new sterile saline and the lenses werereplaced in the respective hybridization oven.

Example 78

Coating Characterized via Captive Bubble Contact Angle Testing. Inanother example, to measure lens contact angles, the captive bubbletechnique was used. The lens was loaded onto a small plate with abulbous feature. The lens was submerged in PBS and suspended atop aplate that has a hole through which the convex surface of the lensprotrudes downward. A blunt needle was placed just below the surface ofthe center of the lens. A bubble was then advanced with a syringe pumpuntil it makes contact with the lens, at which point the bubble wasretracted until it breaks free from either the lens or the needle.Through a magnifying lens, a high-definition video camera records theentire procedure, after which an image was saved from the frameimmediately preceding the moment the bubble detaches from either thelens or the needle. From this image, the angles between the lens and thebubble on both sides of the bubble were calculated in MATLAB and savedas the contact angles for that lens.

Example 79 Lubricity Test Method

A test method was designed and built to observe the affects that thehydrogel coating has on the lubricity of the lens. Three contact lenseswere used in this evaluation:

-   -   1. Packaged silicone hydrogel lens A    -   2. Hydrogel coated silicone hydrogel lens A    -   3. Packaged silicone hydrogel lens B 6 sec

A borosilicate glass plate was cleaned and submerged in a tank of PBS.One end of the plate was raised 30 mm with a shim to create a ramp withan angle of ˜11 degrees. The test lenses were placed at the top of theramp and weighted down with a stainless steel bolt, weightingapproximately 1.13 grams. The lenses were allowed to slide down the ramp˜152 mm and the time required to reach the bottom of the ramp wasrecorded. Results:

Lens Type Time to Slide (sec) Packaged silicone hydrogel lens A Lensallowed to slide for X seconds but only slid down X mm Hydrogel coatedsilicone hydrogel lens A 2 second Packaged silicone hydrogel lens B 6sec 6 seconds

The results of the tests demonstrate a significant increase in lubricityof the lens coated with hydrogel as compared with the uncoated control.

Many of the above examples focus on applying a hydrophilic coating to acontact lens or lens core. However, the methods for applying thehydrophilic coatings can be applied to a variety of other surfacesdisclosed herein using similar process conditions and steps. Thehydrophilic layers applied to non-contact lens materials can havesimilar properties, such as compositions, thicknesses, covalentlybonding to the surface, and cross-linking as the hydrophilic coatingsapplied to the contact lens or lens core.

Example 80

A catheter shaft is processed in accordance with the processes describedherein to form a hydrophilic hydrogel coating on the outer surface ofthe catheter shaft.

Example 81

A stent is processed in accordance with the processes described hereinto form a hydrophilic hydrogel coating on the stent surface.

Example 82

An implantable glucose sensor is processed in accordance with theprocesses described herein to form a hydrophilic hydrogel coating on theouter surface of the implantable glucose sensor.

Example 83

An implantable pacemaker is processed in accordance with the processesdescribed herein to form a hydrophilic hydrogel coating on the outersurface of the pacemaker.

Example 84 Preparation of Polymer Solutions

The coating solution included two components. The first component was apoly(ethylene glycol) (PEG) molecule end functionalized with vinylsulfone groups. The second component was a polyacrylamide molecule withpendant amine functional groups. The polymer solutions were prepared ata concentration of 2.5% in deionized water and then filter sterilizedthrough a 0.45 micron PVDF filter.

Example 85 Preparation of Polymer Solutions

The coating solution included two components. The first component was Apoly(ethylene glycol) (PEG) molecule end functionalized withsuccinimidyl ester groups. The second component was a polyacrylamidemolecule with pendant amine functional groups. The polymer solutionswere prepared at a concentration of 2.5% in deionized water and thenfilter sterilized through a 0.45 micron PVDF filter.

Example 86 Preparation of Polymer Solutions

The coating solution included two components. The first component was apoly(ethylene glycol) (PEG) molecule end functionalized with vinylsulfone groups. The second component was a polyacrylamide molecule withpendant thiol functional groups. The polymer solutions were prepared ata concentration of 2.5% in deionized water and then filter sterilizedthrough a 0.45 micron PVDF filter.

Example 87 Coating a Titanium Surface

A PEG and PAM polymer solution was used to coat a titanium surface. Aplasma treatment was applied to the titanium surface as describedherein. The polymer solution was applied to the titanium surface afterthe plasma surface treatment. The polymer solution was applied through aClick reaction as described herein to deposit a hydrophilic layercomprising PEG and PAM species covalently bound to the titanium surfacethrough the reactive surface sites created by the plasma surfacetreatment.

Example 88 Coating a Stainless Steel Surface

A PEG and PAM polymer solution was used to coat a stainless steelsurface. A plasma treatment was applied to the stainless steel surfaceas described herein. The polymer solution was applied to the stainlesssteel surface after the plasma surface treatment. The polymer solutionwas applied through a Click reaction as described herein to deposit ahydrophilic layer comprising PEG and PAM species covalently bound to thestainless steel surface through the reactive surface sites created bythe plasma surface treatment.

Example 89 Coating a Polypropylene Surface

A PEG and PAM polymer solution was used to coat a polypropylene surface.A plasma treatment was applied to the polypropylene surface as describedherein. The polymer solution was applied to a polypropylene surfaceafter the plasma surface treatment. The polymer solution was appliedthrough a Click reaction as described herein to deposit a hydrophiliclayer comprising PEG and PAM species covalently bound to thepolypropylene surface through the reactive surface sites created by theplasma surface treatment.

Example 90 Coating a Polyamide Surface

A PEG and PAM polymer solution was used to coat a polyamide surface. Aplasma treatment was applied to the polyamide surface as describedherein. The polymer solution was applied to a polyamide surface afterthe plasma surface treatment. The polymer solution was applied through aClick reaction as described herein to deposit a hydrophilic layercomprising PEG and PAM species covalently bound to the polyamide surfacethrough the reactive surface sites created by the plasma surfacetreatment.

Example 91 Coating a Polyester Surface

A PEG and PAM polymer solution was used to coat a polyester surface. Aplasma treatment was applied to the polyester surface as describedherein. The polymer solution was applied to a polyester surface afterthe plasma surface treatment. The polymer solution was applied through aClick reaction as described herein to deposit a hydrophilic layercomprising PEG and PAM species covalently bound to the polyester surfacethrough the reactive surface sites created by the plasma surfacetreatment.

Example 92 Coating a Pebax Surface

A PEG and PAM polymer solution was used to coat a pebax surface. Aplasma treatment was applied to the pebax surface as described herein.The polymer solution was applied to a pebax surface after the plasmasurface treatment. The polymer solution was applied through a Clickreaction as described herein to deposit a hydrophilic layer comprisingPEG and PAM species covalently bound to the pebax surface through thereactive surface sites created by the plasma surface treatment.

Example 93 Coating a Nylon Surface

A PEG and PAM polymer solution was used to coat a nylon surface. Aplasma treatment was applied to the nylon surface as described herein.The polymer solution was applied to a nylon surface after the plasmasurface treatment. The polymer solution was applied through a Clickreaction as described herein to deposit a hydrophilic layer comprisingPEG and PAM species covalently bound to the nylon surface through thereactive surface sites created by the plasma surface treatment.

Example 94 Coating a Nitinol Surface

A PEG and PAM polymer solution was used to coat a nitinol surface. Aplasma treatment was applied to the nitinol surface as described herein.The polymer solution was applied to a nitinol surface after the plasmasurface treatment. The polymer solution was applied through a Clickreaction as described herein to deposit a hydrophilic layer comprisingPEG and PAM species covalently bound to the nitinol surface through thereactive surface sites created by the plasma surface treatment.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical rangerecited herein is intended to include all sub-ranges subsumed therein.

As for additional details pertinent to the present invention, materialsand manufacturing techniques may be employed as within the level ofthose with skill in the relevant art. The same may hold true withrespect to method-based aspects of the invention in terms of additionalacts commonly or logically employed. Also, it is contemplated that anyoptional feature of the inventive variations described may be set forthand claimed independently, or in combination with any one or more of thefeatures described herein. Likewise, reference to a singular item,includes the possibility that there are plural of the same itemspresent. More specifically, as used herein and in the appended claims,the singular forms “a,” “and,” “said,” and “the” include pluralreferents unless the context clearly dictates otherwise. It is furthernoted that the claims may be drafted to exclude any optional element. Assuch, this statement is intended to serve as antecedent basis for use ofsuch exclusive terminology as “solely,” “only” and the like inconnection with the recitation of claim elements, or use of a “negative”limitation. Unless defined otherwise herein, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. The breadth of the present invention is not to be limited bythe subject specification, but rather only by the plain meaning of theclaim terms employed.

What is claimed is:
 1. A medical device comprising: an outer surface;and a hydrogel layer covalently attached to at least a portion of theouter surface, the hydrogel layer adapted to contact a body tissue orfluid, wherein the hydrogel layer comprises a biocompatible polymerpopulation comprising: a first hydrophilic polymer species comprisingpolyethylene glycol (PEG) having between two to twelve branch arms,wherein at least a subset of the branch arms comprises a reactivesulfonyl group, and a second hydrophilic polymer species comprisingpolyacrylamide having one or more pendant reactive nucleophilic groups,wherein the reactive sulfonyl group of at least one of the subset of thebranch arms of the PEG is reacted with the one or more pendant reactivenucleophilic groups of the polyacrylamide to at least partiallycovalently link the PEG to the polyacrylamide.
 2. The device of claim 1,wherein the device is configured to be implantable within a mammalianbody.
 3. The device of claim 2, wherein the device is a stent configuredto keep a cavity open.
 4. The device of claim 3, wherein the stent isconfigured to keep a blood vessel, bile duct, intestine, nasal passageor cavity, sinus cavity, or intraocular channel open.
 5. The device ofclaim 2, wherein the device is a sensor, camera, vital sign monitor,drug depot device, neurostimulator, ultrasound, silicone implant, salineimplant, hernia mesh, penile implant, orthopedic rod or plate or pin ornails, pacemaker, cardiac valve, ear tube, aneurysm coil, or intraocularlens.
 6. The device of claim 1, wherein the device is a test strip. 7.The device of claim 6, wherein the device is a drug, salivary, urine,blood or semen test strip.
 8. The device of claim 1, wherein the deviceis a tool configured to be inserted within a mammalian body.
 9. Thedevice of claim 8, wherein the device is a catheter, trocar, endoscope,or laparoscope.
 10. The device of claim 1, wherein the device isconfigured to be used externally on a mammalian body.
 11. The device ofclaim 10, wherein the device is configured for use as a bandage, wounddressing, external sensor, hearing aid, or artificial skin.
 12. Thedevice of claim 1, wherein the outer surface of the device comprises oneor more of: glass, plastic, titanium, nitinol, polyethylene,polypropylene, polyvinyl chloride, polytetrafluoroethylene,polydimethylsiloxane, polyethylene terephthalate, polyamides, polyetherurethane, polyether urethane urea, polystyrene, polycarbonate,polysulfones, polymethyl methacrylate, poly 2-hydroxyethylmethacrylate,polyvinylalcohol, polyglycolic acid, polycaprolactone, polylactic acid,polyortho ester, cellulose acetate, collagen, or silk.
 13. The device ofclaim 1, wherein the outer surface of the device consists essentially ofa material selected from the group consisting of: glass, plastic,titanium, nitinol, polyethylene, polypropylene, polyvinyl chloride,polytetrafluoroethylene, polydimethylsiloxane, polyethyleneterephthalate, polyamides, polyether urethane, polyether urethane urea,polystyrene, polycarbonate, polysulfones, polymethyl methacrylate, poly2-hydroxyethylmethacrylate, polyvinylalcohol, polyglycolic acid,polycaprolactone, polylactic acid, polyortho ester, cellulose acetate,collagen, or silk.
 14. The device of claim 1, wherein the one or morereactive nucleophilic groups is selected from the group consisting of:amines, amino-reactive groups, sulfhydryl, sulfhydryl-reactive groups,carboxyl groups, hydroxyl groups, haloalkyl groups, dienophile groups,aldehyde or ketone groups, alkenes, epoxides, and phosphoramidites. 15.The device of claim 1, wherein the reactive sulfonyl group of a secondsubset of the branched arms of the PEG is covalently linked to the outersurface of the device.
 16. The device of claim 1, wherein the hydrogellayer substantially surrounds the outer surface of the device.
 17. Thedevice of claim 1, wherein the hydrogel layer or the hydrogel layer anddevice are substantially optically clear.
 18. The device of claim 1,wherein the hydrogel layer is adapted to allow optical transmissionthrough the hydrogel layer to the device.
 19. The device of claim 1,wherein the hydrogel layer is adapted to attenuate x-ray transmission.20. The device of claim 1, wherein the hydrogel layer is adapted toenable diffusion of biologic molecules, glucose, solutes, polymers,drugs.
 21. The device of claim 1, wherein the hydrogel layer comprises athickness between about 5 nm to about 30 nm.
 22. The device of claim 1,wherein the hydrogel layer comprises a thickness below about 100 nm. 23.The device of claim 1, wherein the hydrogel layer comprises a thicknessless than about 50 nm.
 24. The device of claim 1, wherein the hydrogellayer comprises a thickness less than about 1 micron.
 25. The device ofclaim 1, wherein the hydrogel layer comprises a maximum thickness ofabout 10 microns.
 26. The device of claim 1, wherein a first portion ofthe hydrogel layer comprises a first thickness different from a secondthickness of a second portion of the hydrogel layer.
 27. The device ofclaim 1, wherein the hydrogel layer has a lower coefficient of frictionthan an underlying device surface.
 28. The device of claim 1, whereinthe hydrogel layer has a relative protein resistance compared to anunderlying device surface.
 29. The device of claim 1, wherein thehydrogel layer comprises between about 80% to about 98% water by weight.